Full text data of S100A8
S100A8
(CAGA, CFAG, MRP8)
[Confidence: low (only semi-automatic identification from reviews)]
Protein S100-A8 (Calgranulin-A; Calprotectin L1L subunit; Cystic fibrosis antigen; CFAG; Leukocyte L1 complex light chain; Migration inhibitory factor-related protein 8; MRP-8; p8; S100 calcium-binding protein A8; Urinary stone protein band A; Protein S100-A8, N-terminally processed)
Protein S100-A8 (Calgranulin-A; Calprotectin L1L subunit; Cystic fibrosis antigen; CFAG; Leukocyte L1 complex light chain; Migration inhibitory factor-related protein 8; MRP-8; p8; S100 calcium-binding protein A8; Urinary stone protein band A; Protein S100-A8, N-terminally processed)
UniProt
P05109
ID S10A8_HUMAN Reviewed; 93 AA.
AC P05109; A8K5L3; D3DV37; Q5SY70; Q9UC84; Q9UC92; Q9UCJ0; Q9UCM6;
read moreDT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1988, sequence version 1.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Protein S100-A8;
DE AltName: Full=Calgranulin-A;
DE AltName: Full=Calprotectin L1L subunit;
DE AltName: Full=Cystic fibrosis antigen;
DE Short=CFAG;
DE AltName: Full=Leukocyte L1 complex light chain;
DE AltName: Full=Migration inhibitory factor-related protein 8;
DE Short=MRP-8;
DE Short=p8;
DE AltName: Full=S100 calcium-binding protein A8;
DE AltName: Full=Urinary stone protein band A;
DE Contains:
DE RecName: Full=Protein S100-A8, N-terminally processed;
GN Name=S100A8; Synonyms=CAGA, CFAG, MRP8;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3561500; DOI=10.1038/326614a0;
RA Dorin J.R., Novak M., Hill R.E., Brock D.J.H., Secher D.S.,
RA van Heyningen V.;
RT "A clue to the basic defect in cystic fibrosis from cloning the CF
RT antigen gene.";
RL Nature 326:614-617(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3313057; DOI=10.1038/330080a0;
RA Odink K., Cerletti N., Bruggen J., Clerc R.G., Tarcsay L., Zwaldo G.,
RA Gerhards G., Schlegel R., Sorg C.;
RT "Two calcium-binding proteins in infiltrate macrophages of rheumatoid
RT arthritis.";
RL Nature 330:80-82(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3405210;
RA Lagasse E., Clerc R.G.;
RT "Cloning and expression of two human genes encoding calcium-binding
RT proteins that are regulated during myeloid differentiation.";
RL Mol. Cell. Biol. 8:2402-2410(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 1-30.
RX PubMed=2039599;
RA Schaefer T., Sachse G.E., Gassen H.G.;
RT "The calcium-binding protein MRP-8 is produced by human pulmonary
RT tumor cells.";
RL Biol. Chem. Hoppe-Seyler 372:1-4(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 1-19; 24-35 AND 63-89.
RX PubMed=8619876; DOI=10.1006/bbrc.1996.0616;
RA Marti T., Erttmann K.D., Gallin M.Y.;
RT "Host-parasite interaction in human onchocerciasis: identification and
RT sequence analysis of a novel human calgranulin.";
RL Biochem. Biophys. Res. Commun. 221:454-458(1996).
RN [12]
RP PROTEIN SEQUENCE OF 1-27.
RX PubMed=8423249;
RA Miyasaki K.T., Bodeau A.L., Murthy A.R., Lehrer R.I.;
RT "In vitro antimicrobial activity of the human neutrophil cytosolic S-
RT 100 protein complex, calprotectin, against Capnocytophaga sputigena.";
RL J. Dent. Res. 72:517-523(1993).
RN [13]
RP PROTEIN SEQUENCE OF 1-25.
RC TISSUE=Neutrophil;
RX PubMed=1326551;
RA Lemarchand P., Vaglio M., Mauel J., Markert M.;
RT "Translocation of a small cytosolic calcium-binding protein (MRP-8) to
RT plasma membrane correlates with human neutrophil activation.";
RL J. Biol. Chem. 267:19379-19382(1992).
RN [14]
RP PROTEIN SEQUENCE OF 1-20.
RX PubMed=7849642;
RA Umekawa T., Kurita T.;
RT "Calprotectin-like protein is related to soluble organic matrix in
RT calcium oxalate urinary stone.";
RL Biochem. Mol. Biol. Int. 34:309-313(1994).
RN [15]
RP PROTEIN SEQUENCE OF 1-20.
RC TISSUE=Ascites;
RX PubMed=7695842;
RA Nakai M., Ishikawa M., Hamada Y., Sugano S.;
RT "Isolation of an ascitic oncodevelopmental protein exhibiting high
RT sequence homology with calcium-binding protein MRP8.";
RL Biol. Chem. Hoppe-Seyler 375:789-792(1994).
RN [16]
RP PROTEIN SEQUENCE OF 38-47 AND 50-56.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [17]
RP SUBCELLULAR LOCATION, SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=9083090; DOI=10.1074/jbc.272.14.9496;
RA Rammes A., Roth J., Goebeler M., Klempt M., Hartmann M., Sorg C.;
RT "Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins
RT of the S100 family, are secreted by activated monocytes via a novel,
RT tubulin-dependent pathway.";
RL J. Biol. Chem. 272:9496-9502(1997).
RN [18]
RP INTERACTION WITH CEACAM3.
RX PubMed=11708798; DOI=10.1006/bbrc.2001.5955;
RA Streichert T., Ebrahimnejad A., Ganzer S., Flayeh R., Wagener C.,
RA Bruemmer J.;
RT "The microbial receptor CEACAM3 is linked to the calprotectin complex
RT in granulocytes.";
RL Biochem. Biophys. Res. Commun. 289:191-197(2001).
RN [19]
RP FUNCTION.
RX PubMed=12626582;
RA Ryckman C., Vandal K., Rouleau P., Talbot M., Tessier P.A.;
RT "Proinflammatory activities of S100: proteins S100A8, S100A9, and
RT S100A8/A9 induce neutrophil chemotaxis and adhesion.";
RL J. Immunol. 170:3233-3242(2003).
RN [20]
RP FUNCTION, AND INTERACTION WITH TUBULIN.
RX PubMed=15331440; DOI=10.1182/blood-2004-02-0446;
RA Vogl T., Ludwig S., Goebeler M., Strey A., Thorey I.S., Reichelt R.,
RA Foell D., Gerke V., Manitz M.P., Nacken W., Werner S., Sorg C.,
RA Roth J.;
RT "MRP8 and MRP14 control microtubule reorganization during
RT transendothelial migration of phagocytes.";
RL Blood 104:4260-4268(2004).
RN [21]
RP FUNCTION, MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=15598812; DOI=10.1182/blood-2004-07-2520;
RA Viemann D., Strey A., Janning A., Jurk K., Klimmek K., Vogl T.,
RA Hirono K., Ichida F., Foell D., Kehrel B., Gerke V., Sorg C., Roth J.;
RT "Myeloid-related proteins 8 and 14 induce a specific inflammatory
RT response in human microvascular endothelial cells.";
RL Blood 105:2955-2962(2005).
RN [22]
RP FUNCTION, AND INTERACTION WITH NCF2/P67PHOX; RAC1 AND RAC2.
RX PubMed=15642721; DOI=10.1096/fj.04-2377fje;
RA Kerkhoff C., Nacken W., Benedyk M., Dagher M.C., Sopalla C.,
RA Doussiere J.;
RT "The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase
RT activation by interaction with p67phox and Rac-2.";
RL FASEB J. 19:467-469(2005).
RN [23]
RP FUNCTION, INHIBITION BY ZINC IONS, AND SUBUNIT.
RX PubMed=16258195; DOI=10.1155/MI.2005.280;
RA Nakatani Y., Yamazaki M., Chazin W.J., Yui S.;
RT "Regulation of S100A8/A9 (calprotectin) binding to tumor cells by zinc
RT ion and its implication for apoptosis-inducing activity.";
RL Mediators Inflamm. 2005:280-292(2005).
RN [24]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH ANXA6.
RX PubMed=18786929; DOI=10.1074/jbc.M803908200;
RA Bode G., Lueken A., Kerkhoff C., Roth J., Ludwig S., Nacken W.;
RT "Interaction between S100A8/A9 and annexin A6 is involved in the
RT calcium-induced cell surface exposition of S100A8/A9.";
RL J. Biol. Chem. 283:31776-31784(2008).
RN [25]
RP S-NITROSYLATION AT CYS-42.
RX PubMed=18832721;
RA Lim S.Y., Raftery M., Cai H., Hsu K., Yan W.X., Hseih H.L.,
RA Watts R.N., Richardson D., Thomas S., Perry M., Geczy C.L.;
RT "S-nitrosylated S100A8: novel anti-inflammatory properties.";
RL J. Immunol. 181:5627-5636(2008).
RN [26]
RP REVIEW.
RX PubMed=20523765;
RA Hsu K., Champaiboon C., Guenther B.D., Sorenson B.S., Khammanivong A.,
RA Ross K.F., Geczy C.L., Herzberg M.C.;
RT "Anti-infective protective properties of S100 calgranulins.";
RL Antiinflamm. Antiallergy Agents Med. Chem. 8:290-305(2009).
RN [27]
RP REVIEW.
RX PubMed=19835859; DOI=10.1016/j.ejphar.2009.08.044;
RA Ghavami S., Chitayat S., Hashemi M., Eshraghi M., Chazin W.J.,
RA Halayko A.J., Kerkhoff C.;
RT "S100A8/A9: a Janus-faced molecule in cancer therapy and
RT tumorgenesis.";
RL Eur. J. Pharmacol. 625:73-83(2009).
RN [28]
RP FUNCTION, AND MUTAGENESIS OF CYS-42.
RX PubMed=19087201; DOI=10.1111/j.1574-695X.2008.00498.x;
RA Sroussi H.Y., Koehler G.A., Agabian N., Villines D., Palefsky J.M.;
RT "Substitution of methionine 63 or 83 in S100A9 and cysteine 42 in
RT S100A8 abrogate the antifungal activities of S100A8/A9: potential role
RT for oxidative regulation.";
RL FEMS Immunol. Med. Microbiol. 55:55-61(2009).
RN [29]
RP FUNCTION, AND SUBUNIT.
RX PubMed=19122197; DOI=10.1074/jbc.M806605200;
RA Champaiboon C., Sappington K.J., Guenther B.D., Ross K.F.,
RA Herzberg M.C.;
RT "Calprotectin S100A9 calcium-binding loops I and II are essential for
RT keratinocyte resistance to bacterial invasion.";
RL J. Biol. Chem. 284:7078-7090(2009).
RN [30]
RP REVIEW.
RX PubMed=19451397; DOI=10.1189/jlb.1008647;
RA Ehrchen J.M., Sunderkoetter C., Foell D., Vogl T., Roth J.;
RT "The endogenous Toll-like receptor 4 agonist S100A8/S100A9
RT (calprotectin) as innate amplifier of infection, autoimmunity, and
RT cancer.";
RL J. Leukoc. Biol. 86:557-566(2009).
RN [31]
RP FUNCTION.
RX PubMed=19935772; DOI=10.1038/cr.2009.129;
RA Ghavami S., Eshragi M., Ande S.R., Chazin W.J., Klonisch T.,
RA Halayko A.J., McNeill K.D., Hashemi M., Kerkhoff C., Los M.;
RT "S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk
RT between mitochondria and lysosomes that involves BNIP3.";
RL Cell Res. 20:314-331(2010).
RN [32]
RP REVIEW.
RX PubMed=19935766; DOI=10.1038/icb.2009.88;
RA Perera C., McNeil H.P., Geczy C.L.;
RT "S100 Calgranulins in inflammatory arthritis.";
RL Immunol. Cell Biol. 88:41-49(2010).
RN [33]
RP REVIEW.
RX PubMed=20213444; DOI=10.1007/s00726-010-0528-0;
RA Goyette J., Geczy C.L.;
RT "Inflammation-associated S100 proteins: new mechanisms that regulate
RT function.";
RL Amino Acids 41:821-842(2011).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [35]
RP REVIEW.
RX PubMed=22095980; DOI=10.1161/ATVBAHA.111.236927;
RA Averill M.M., Kerkhoff C., Bornfeldt K.E.;
RT "S100A8 and S100A9 in cardiovascular biology and disease.";
RL Arterioscler. Thromb. Vasc. Biol. 32:223-229(2012).
RN [36]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=21487906; DOI=10.1007/s10753-011-9330-8;
RA Koike A., Arai S., Yamada S., Nagae A., Saita N., Itoh H., Uemoto S.,
RA Totani M., Ikemoto M.;
RT "Dynamic mobility of immunological cells expressing S100A8 and S100A9
RT in vivo: a variety of functional roles of the two proteins as
RT regulators in acute inflammatory reaction.";
RL Inflammation 35:409-419(2012).
RN [37]
RP REVIEW.
RX PubMed=22489132; DOI=10.3390/ijms13032893;
RA Vogl T., Gharibyan A.L., Morozova-Roche L.A.;
RT "Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into
RT multifunctional native and amyloid complexes.";
RL Int. J. Mol. Sci. 13:2893-2917(2012).
RN [38]
RP REVIEW.
RX PubMed=21912088; DOI=10.1159/000330095;
RA Srikrishna G.;
RT "S100A8 and S100A9: new insights into their roles in malignancy.";
RL J. Innate Immun. 4:31-40(2012).
RN [39]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CYBA AND CYBB.
RX PubMed=22808130; DOI=10.1371/journal.pone.0040277;
RA Berthier S., Nguyen M.V., Baillet A., Hograindleur M.A., Paclet M.H.,
RA Polack B., Morel F.;
RT "Molecular interface of S100A8 with cytochrome b and NADPH oxidase
RT activation.";
RL PLoS ONE 7:E40277-E40277(2012).
RN [40]
RP FUNCTION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=22363402; DOI=10.1371/journal.pone.0029333;
RA Atallah M., Krispin A., Trahtemberg U., Ben-Hamron S., Grau A.,
RA Verbovetski I., Mevorach D.;
RT "Constitutive neutrophil apoptosis: regulation by cell concentration
RT via S100 A8/9 and the MEK-ERK pathway.";
RL PLoS ONE 7:E29333-E29333(2012).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
RX PubMed=10771424; DOI=10.1107/S0907444900002833;
RA Ishikawa K., Nakagawa A., Tanaka I., Suzuki M., Nishihira J.;
RT "The structure of human MRP8, a member of the S100 calcium-binding
RT protein family, by MAD phasing at 1.9 A resolution.";
RL Acta Crystallogr. D 56:559-566(2000).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH S100A9, SUBUNIT,
RP AND ZINC-BINDING.
RX PubMed=17553524; DOI=10.1016/j.jmb.2007.04.065;
RA Korndoerfer I.P., Brueckner F., Skerra A.;
RT "The crystal structure of the human (S100A8/S100A9)2 heterotetramer,
RT calprotectin, illustrates how conformational changes of interacting
RT alpha-helices can determine specific association of two EF-hand
RT proteins.";
RL J. Mol. Biol. 370:887-898(2007).
CC -!- FUNCTION: S100A8 is a calcium- and zinc-binding protein which
CC plays a prominent role in the regulation of inflammatory processes
CC and immune response. It can induce neutrophil chemotaxis and
CC adhesion. Predominantly found as calprotectin (S100A8/A9) which
CC has a wide plethora of intra- and extracellular functions. The
CC intracellular functions include: facilitating leukocyte
CC arachidonic acid trafficking and metabolism, modulation of the
CC tubulin-dependent cytoskeleton during migration of phagocytes and
CC activation of the neutrophilic NADPH-oxidase. Activates NADPH-
CC oxidase by facilitating the enzyme complex assembly at the cell
CC membrane, transfering arachidonic acid, an essential cofactor, to
CC the enzyme complex and S100A8 contributes to the enzyme assembly
CC by directly binding to NCF2/P67PHOX. The extracellular functions
CC involve proinfammatory, antimicrobial, oxidant-scavenging and
CC apoptosis-inducing activities. Its proinflammatory activity
CC includes recruitment of leukocytes, promotion of cytokine and
CC chemokine production, and regulation of leukocyte adhesion and
CC migration. Acts as an alarmin or a danger associated molecular
CC pattern (DAMP) molecule and stimulates innate immune cells via
CC binding to pattern recognition receptors such as Toll-like
CC receptor 4 (TLR4) and receptor for advanced glycation endproducts
CC (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-
CC kappa-B signaling pathways resulting in the amplification of the
CC proinflammatory cascade. Has antimicrobial activity towards
CC bacteria and fungi and exerts its antimicrobial activity probably
CC via chelation of Zn(2+) which is essential for microbial growth.
CC Can induce cell death via autophagy and apoptosis and this occurs
CC through the cross-talk of mitochondria and lysosomes via reactive
CC oxygen species (ROS) and the process involves BNIP3. Can regulate
CC neutrophil number and apoptosis by an anti-apoptotic effect;
CC regulates cell survival via ITGAM/ITGB and TLR4 and a signaling
CC mechanism involving MEK-ERK. Its role as an oxidant scavenger has
CC a protective role in preventing exaggerated tissue damage by
CC scavenging oxidants. Can act as a potent amplifier of inflammation
CC in autoimmunity as well as in cancer development and tumor spread.
CC -!- SUBUNIT: Homodimer. Preferentially exists as a heterodimer or
CC heterotetramer with S100A9 known as calprotectin (S100A8/A9).
CC S100A8 interacts with AGER, ATP2A2 and with the heterodimeric
CC complex formed by TLR4 and LY96 (By similarity). Calprotectin
CC (S100A8/9) interacts with CEACAM3 and tubulin filaments in a
CC calcium-dependent manner. Heterotetrameric calprotectin
CC (S100A8/A9) interacts with ANXA6 and associates with tubulin
CC filaments in activated monocytes. S100A8 and calprotectin
CC (S100A8/9) interact with NCF2/P67PHOX, RAC1 and RAC2. Calprotectin
CC (S100A8/9) interacts with CYBA and CYBB.
CC -!- INTERACTION:
CC P06702:S100A9; NbExp=3; IntAct=EBI-355281, EBI-1055001;
CC -!- SUBCELLULAR LOCATION: Secreted. Cytoplasm. Cytoplasm,
CC cytoskeleton. Cell membrane; Peripheral membrane protein.
CC Note=Predominantly localized in the cytoplasm. Upon elevation of
CC the intracellular calcium level, translocated from the cytoplasm
CC to the cytoskeleton and the cell membrane. Upon neutrophil
CC activation or endothelial adhesion of monocytes, is secreted via a
CC microtubule-mediated, alternative pathway.
CC -!- TISSUE SPECIFICITY: Calprotectin (S100A8/9) is predominantly
CC expressed in myeloid cells. Except for inflammatory conditions,
CC the expression is restricted to a specific stage of myeloid
CC differentiation since both proteins are expressed in circulating
CC neutrophils and monocytes but are absent in normal tissue
CC macrophages and lymphocytes. Under chronic inflammatory
CC conditions, such as psoriasis and malignant disorders, also
CC expressed in the epidermis. Found in high concentrations at local
CC sites of inflammation or in the serum of patients with
CC inflammatory diseases such as rheumatoid, cystic fibrosis,
CC inflammatory bowel disease, Crohn's disease, giant cell arteritis,
CC cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus,
CC and progressive systemic sclerosis. Involved in the formation and
CC deposition of amyloids in the aging prostate known as corpora
CC amylacea inclusions. Strongly up-regulated in many tumors,
CC including gastric, esophageal, colon, pancreatic, bladder,
CC ovarian, thyroid, breast and skin cancers.
CC -!- MISCELLANEOUS: Binds two calcium ions per molecule with an
CC affinity similar to that of the S100 proteins.
CC -!- SIMILARITY: Belongs to the S-100 family.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/S100A8ID46446ch1q21.html";
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DR EMBL; Y00278; CAA68390.1; -; mRNA.
DR EMBL; X06234; CAA29580.1; -; mRNA.
DR EMBL; M21005; AAA36327.1; -; Genomic_DNA.
DR EMBL; AK291328; BAF84017.1; -; mRNA.
DR EMBL; CR407674; CAG28602.1; -; mRNA.
DR EMBL; BT007378; AAP36042.1; -; mRNA.
DR EMBL; AL591704; CAI19497.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53330.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53331.1; -; Genomic_DNA.
DR EMBL; BC005928; AAH05928.1; -; mRNA.
DR PIR; A31848; BCHUCF.
DR RefSeq; NP_002955.2; NM_002964.4.
DR UniGene; Hs.416073; -.
DR PDB; 1MR8; X-ray; 1.90 A; A/B=1-93.
DR PDB; 1XK4; X-ray; 1.80 A; A/B/E/F/I/J=1-93.
DR PDB; 4GGF; X-ray; 1.60 A; A/K/S/U=1-93.
DR PDBsum; 1MR8; -.
DR PDBsum; 1XK4; -.
DR PDBsum; 4GGF; -.
DR ProteinModelPortal; P05109; -.
DR SMR; P05109; 1-90.
DR DIP; DIP-1165N; -.
DR IntAct; P05109; 31.
DR MINT; MINT-1151603; -.
DR STRING; 9606.ENSP00000357721; -.
DR PhosphoSite; P05109; -.
DR DMDM; 115442; -.
DR SWISS-2DPAGE; P05109; -.
DR PaxDb; P05109; -.
DR PeptideAtlas; P05109; -.
DR PRIDE; P05109; -.
DR DNASU; 6279; -.
DR Ensembl; ENST00000368732; ENSP00000357721; ENSG00000143546.
DR Ensembl; ENST00000368733; ENSP00000357722; ENSG00000143546.
DR GeneID; 6279; -.
DR KEGG; hsa:6279; -.
DR UCSC; uc001fbs.3; human.
DR CTD; 6279; -.
DR GeneCards; GC01M153362; -.
DR HGNC; HGNC:10498; S100A8.
DR HPA; CAB002791; -.
DR HPA; HPA024372; -.
DR MIM; 123885; gene.
DR neXtProt; NX_P05109; -.
DR PharmGKB; PA34910; -.
DR eggNOG; NOG39611; -.
DR HOVERGEN; HBG001479; -.
DR InParanoid; P05109; -.
DR OMA; DTWFKEL; -.
DR OrthoDB; EOG76HQ48; -.
DR PhylomeDB; P05109; -.
DR ChiTaRS; S100A8; human.
DR EvolutionaryTrace; P05109; -.
DR GeneWiki; S100_calcium_binding_protein_A8; -.
DR GenomeRNAi; 6279; -.
DR NextBio; 24373; -.
DR PRO; PR:P05109; -.
DR Bgee; P05109; -.
DR CleanEx; HS_S100A8; -.
DR Genevestigator; P05109; -.
DR GO; GO:0005856; C:cytoskeleton; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:UniProtKB.
DR GO; GO:0050544; F:arachidonic acid binding; TAS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; TAS:UniProtKB.
DR GO; GO:0008017; F:microtubule binding; TAS:UniProtKB.
DR GO; GO:0050786; F:RAGE receptor binding; TAS:UniProtKB.
DR GO; GO:0035662; F:Toll-like receptor 4 binding; TAS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; TAS:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0002526; P:acute inflammatory response; IEA:Ensembl.
DR GO; GO:0006914; P:autophagy; IDA:UniProtKB.
DR GO; GO:0032602; P:chemokine production; TAS:UniProtKB.
DR GO; GO:0002544; P:chronic inflammatory response; IEA:Ensembl.
DR GO; GO:0042742; P:defense response to bacterium; TAS:UniProtKB.
DR GO; GO:0050832; P:defense response to fungus; TAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002523; P:leukocyte migration involved in inflammatory response; IDA:UniProtKB.
DR GO; GO:0070488; P:neutrophil aggregation; IDA:UniProtKB.
DR GO; GO:0030593; P:neutrophil chemotaxis; IDA:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; TAS:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:UniProtKB.
DR GO; GO:0051493; P:regulation of cytoskeleton organization; TAS:UniProtKB.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR GO; GO:0032119; P:sequestering of zinc ion; TAS:UniProtKB.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR001751; S100/CaBP-9k_CS.
DR InterPro; IPR013787; S100_Ca-bd_sub.
DR InterPro; IPR028474; S100A8.
DR PANTHER; PTHR11639:SF5; PTHR11639:SF5; 1.
DR Pfam; PF01023; S_100; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
DR PROSITE; PS00303; S100_CABP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antimicrobial; Apoptosis; Autophagy; Calcium;
KW Cell membrane; Chemotaxis; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Immunity; Inflammatory response;
KW Innate immunity; Membrane; Metal-binding; Reference proteome; Repeat;
KW S-nitrosylation; Secreted; Zinc.
FT CHAIN 1 93 Protein S100-A8.
FT /FTId=PRO_0000143993.
FT INIT_MET 1 1 Removed; alternate (By similarity).
FT CHAIN 2 93 Protein S100-A8, N-terminally processed.
FT /FTId=PRO_0000421773.
FT DOMAIN 12 47 EF-hand 1.
FT DOMAIN 46 81 EF-hand 2.
FT CA_BIND 20 33 1; low affinity.
FT CA_BIND 59 70 2; high affinity.
FT METAL 17 17 Zinc (Probable).
FT METAL 27 27 Zinc (Probable).
FT METAL 83 83 Zinc (Probable).
FT METAL 87 87 Zinc (Probable).
FT MOD_RES 42 42 S-nitrosocysteine.
FT MUTAGEN 42 42 C->A: Loss of antifungal activity.
FT CONFLICT 80 93 VAAHKKSHEESHKE -> WQPTKKAMKKATKSS (in
FT Ref. 1; CAA68390).
FT HELIX 4 20
FT STRAND 22 25
FT HELIX 31 41
FT HELIX 44 47
FT HELIX 51 58
FT STRAND 63 66
FT HELIX 68 86
SQ SEQUENCE 93 AA; 10835 MW; 78F589140B9CE166 CRC64;
MLTELEKALN SIIDVYHKYS LIKGNFHAVY RDDLKKLLET ECPQYIRKKG ADVWFKELDI
NTDGAVNFQE FLILVIKMGV AAHKKSHEES HKE
//
ID S10A8_HUMAN Reviewed; 93 AA.
AC P05109; A8K5L3; D3DV37; Q5SY70; Q9UC84; Q9UC92; Q9UCJ0; Q9UCM6;
read moreDT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1988, sequence version 1.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Protein S100-A8;
DE AltName: Full=Calgranulin-A;
DE AltName: Full=Calprotectin L1L subunit;
DE AltName: Full=Cystic fibrosis antigen;
DE Short=CFAG;
DE AltName: Full=Leukocyte L1 complex light chain;
DE AltName: Full=Migration inhibitory factor-related protein 8;
DE Short=MRP-8;
DE Short=p8;
DE AltName: Full=S100 calcium-binding protein A8;
DE AltName: Full=Urinary stone protein band A;
DE Contains:
DE RecName: Full=Protein S100-A8, N-terminally processed;
GN Name=S100A8; Synonyms=CAGA, CFAG, MRP8;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3561500; DOI=10.1038/326614a0;
RA Dorin J.R., Novak M., Hill R.E., Brock D.J.H., Secher D.S.,
RA van Heyningen V.;
RT "A clue to the basic defect in cystic fibrosis from cloning the CF
RT antigen gene.";
RL Nature 326:614-617(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3313057; DOI=10.1038/330080a0;
RA Odink K., Cerletti N., Bruggen J., Clerc R.G., Tarcsay L., Zwaldo G.,
RA Gerhards G., Schlegel R., Sorg C.;
RT "Two calcium-binding proteins in infiltrate macrophages of rheumatoid
RT arthritis.";
RL Nature 330:80-82(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3405210;
RA Lagasse E., Clerc R.G.;
RT "Cloning and expression of two human genes encoding calcium-binding
RT proteins that are regulated during myeloid differentiation.";
RL Mol. Cell. Biol. 8:2402-2410(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 1-30.
RX PubMed=2039599;
RA Schaefer T., Sachse G.E., Gassen H.G.;
RT "The calcium-binding protein MRP-8 is produced by human pulmonary
RT tumor cells.";
RL Biol. Chem. Hoppe-Seyler 372:1-4(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 1-19; 24-35 AND 63-89.
RX PubMed=8619876; DOI=10.1006/bbrc.1996.0616;
RA Marti T., Erttmann K.D., Gallin M.Y.;
RT "Host-parasite interaction in human onchocerciasis: identification and
RT sequence analysis of a novel human calgranulin.";
RL Biochem. Biophys. Res. Commun. 221:454-458(1996).
RN [12]
RP PROTEIN SEQUENCE OF 1-27.
RX PubMed=8423249;
RA Miyasaki K.T., Bodeau A.L., Murthy A.R., Lehrer R.I.;
RT "In vitro antimicrobial activity of the human neutrophil cytosolic S-
RT 100 protein complex, calprotectin, against Capnocytophaga sputigena.";
RL J. Dent. Res. 72:517-523(1993).
RN [13]
RP PROTEIN SEQUENCE OF 1-25.
RC TISSUE=Neutrophil;
RX PubMed=1326551;
RA Lemarchand P., Vaglio M., Mauel J., Markert M.;
RT "Translocation of a small cytosolic calcium-binding protein (MRP-8) to
RT plasma membrane correlates with human neutrophil activation.";
RL J. Biol. Chem. 267:19379-19382(1992).
RN [14]
RP PROTEIN SEQUENCE OF 1-20.
RX PubMed=7849642;
RA Umekawa T., Kurita T.;
RT "Calprotectin-like protein is related to soluble organic matrix in
RT calcium oxalate urinary stone.";
RL Biochem. Mol. Biol. Int. 34:309-313(1994).
RN [15]
RP PROTEIN SEQUENCE OF 1-20.
RC TISSUE=Ascites;
RX PubMed=7695842;
RA Nakai M., Ishikawa M., Hamada Y., Sugano S.;
RT "Isolation of an ascitic oncodevelopmental protein exhibiting high
RT sequence homology with calcium-binding protein MRP8.";
RL Biol. Chem. Hoppe-Seyler 375:789-792(1994).
RN [16]
RP PROTEIN SEQUENCE OF 38-47 AND 50-56.
RC TISSUE=Keratinocyte;
RX PubMed=1286667; DOI=10.1002/elps.11501301199;
RA Rasmussen H.H., van Damme J., Puype M., Gesser B., Celis J.E.,
RA Vandekerckhove J.;
RT "Microsequences of 145 proteins recorded in the two-dimensional gel
RT protein database of normal human epidermal keratinocytes.";
RL Electrophoresis 13:960-969(1992).
RN [17]
RP SUBCELLULAR LOCATION, SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=9083090; DOI=10.1074/jbc.272.14.9496;
RA Rammes A., Roth J., Goebeler M., Klempt M., Hartmann M., Sorg C.;
RT "Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins
RT of the S100 family, are secreted by activated monocytes via a novel,
RT tubulin-dependent pathway.";
RL J. Biol. Chem. 272:9496-9502(1997).
RN [18]
RP INTERACTION WITH CEACAM3.
RX PubMed=11708798; DOI=10.1006/bbrc.2001.5955;
RA Streichert T., Ebrahimnejad A., Ganzer S., Flayeh R., Wagener C.,
RA Bruemmer J.;
RT "The microbial receptor CEACAM3 is linked to the calprotectin complex
RT in granulocytes.";
RL Biochem. Biophys. Res. Commun. 289:191-197(2001).
RN [19]
RP FUNCTION.
RX PubMed=12626582;
RA Ryckman C., Vandal K., Rouleau P., Talbot M., Tessier P.A.;
RT "Proinflammatory activities of S100: proteins S100A8, S100A9, and
RT S100A8/A9 induce neutrophil chemotaxis and adhesion.";
RL J. Immunol. 170:3233-3242(2003).
RN [20]
RP FUNCTION, AND INTERACTION WITH TUBULIN.
RX PubMed=15331440; DOI=10.1182/blood-2004-02-0446;
RA Vogl T., Ludwig S., Goebeler M., Strey A., Thorey I.S., Reichelt R.,
RA Foell D., Gerke V., Manitz M.P., Nacken W., Werner S., Sorg C.,
RA Roth J.;
RT "MRP8 and MRP14 control microtubule reorganization during
RT transendothelial migration of phagocytes.";
RL Blood 104:4260-4268(2004).
RN [21]
RP FUNCTION, MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=15598812; DOI=10.1182/blood-2004-07-2520;
RA Viemann D., Strey A., Janning A., Jurk K., Klimmek K., Vogl T.,
RA Hirono K., Ichida F., Foell D., Kehrel B., Gerke V., Sorg C., Roth J.;
RT "Myeloid-related proteins 8 and 14 induce a specific inflammatory
RT response in human microvascular endothelial cells.";
RL Blood 105:2955-2962(2005).
RN [22]
RP FUNCTION, AND INTERACTION WITH NCF2/P67PHOX; RAC1 AND RAC2.
RX PubMed=15642721; DOI=10.1096/fj.04-2377fje;
RA Kerkhoff C., Nacken W., Benedyk M., Dagher M.C., Sopalla C.,
RA Doussiere J.;
RT "The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase
RT activation by interaction with p67phox and Rac-2.";
RL FASEB J. 19:467-469(2005).
RN [23]
RP FUNCTION, INHIBITION BY ZINC IONS, AND SUBUNIT.
RX PubMed=16258195; DOI=10.1155/MI.2005.280;
RA Nakatani Y., Yamazaki M., Chazin W.J., Yui S.;
RT "Regulation of S100A8/A9 (calprotectin) binding to tumor cells by zinc
RT ion and its implication for apoptosis-inducing activity.";
RL Mediators Inflamm. 2005:280-292(2005).
RN [24]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH ANXA6.
RX PubMed=18786929; DOI=10.1074/jbc.M803908200;
RA Bode G., Lueken A., Kerkhoff C., Roth J., Ludwig S., Nacken W.;
RT "Interaction between S100A8/A9 and annexin A6 is involved in the
RT calcium-induced cell surface exposition of S100A8/A9.";
RL J. Biol. Chem. 283:31776-31784(2008).
RN [25]
RP S-NITROSYLATION AT CYS-42.
RX PubMed=18832721;
RA Lim S.Y., Raftery M., Cai H., Hsu K., Yan W.X., Hseih H.L.,
RA Watts R.N., Richardson D., Thomas S., Perry M., Geczy C.L.;
RT "S-nitrosylated S100A8: novel anti-inflammatory properties.";
RL J. Immunol. 181:5627-5636(2008).
RN [26]
RP REVIEW.
RX PubMed=20523765;
RA Hsu K., Champaiboon C., Guenther B.D., Sorenson B.S., Khammanivong A.,
RA Ross K.F., Geczy C.L., Herzberg M.C.;
RT "Anti-infective protective properties of S100 calgranulins.";
RL Antiinflamm. Antiallergy Agents Med. Chem. 8:290-305(2009).
RN [27]
RP REVIEW.
RX PubMed=19835859; DOI=10.1016/j.ejphar.2009.08.044;
RA Ghavami S., Chitayat S., Hashemi M., Eshraghi M., Chazin W.J.,
RA Halayko A.J., Kerkhoff C.;
RT "S100A8/A9: a Janus-faced molecule in cancer therapy and
RT tumorgenesis.";
RL Eur. J. Pharmacol. 625:73-83(2009).
RN [28]
RP FUNCTION, AND MUTAGENESIS OF CYS-42.
RX PubMed=19087201; DOI=10.1111/j.1574-695X.2008.00498.x;
RA Sroussi H.Y., Koehler G.A., Agabian N., Villines D., Palefsky J.M.;
RT "Substitution of methionine 63 or 83 in S100A9 and cysteine 42 in
RT S100A8 abrogate the antifungal activities of S100A8/A9: potential role
RT for oxidative regulation.";
RL FEMS Immunol. Med. Microbiol. 55:55-61(2009).
RN [29]
RP FUNCTION, AND SUBUNIT.
RX PubMed=19122197; DOI=10.1074/jbc.M806605200;
RA Champaiboon C., Sappington K.J., Guenther B.D., Ross K.F.,
RA Herzberg M.C.;
RT "Calprotectin S100A9 calcium-binding loops I and II are essential for
RT keratinocyte resistance to bacterial invasion.";
RL J. Biol. Chem. 284:7078-7090(2009).
RN [30]
RP REVIEW.
RX PubMed=19451397; DOI=10.1189/jlb.1008647;
RA Ehrchen J.M., Sunderkoetter C., Foell D., Vogl T., Roth J.;
RT "The endogenous Toll-like receptor 4 agonist S100A8/S100A9
RT (calprotectin) as innate amplifier of infection, autoimmunity, and
RT cancer.";
RL J. Leukoc. Biol. 86:557-566(2009).
RN [31]
RP FUNCTION.
RX PubMed=19935772; DOI=10.1038/cr.2009.129;
RA Ghavami S., Eshragi M., Ande S.R., Chazin W.J., Klonisch T.,
RA Halayko A.J., McNeill K.D., Hashemi M., Kerkhoff C., Los M.;
RT "S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk
RT between mitochondria and lysosomes that involves BNIP3.";
RL Cell Res. 20:314-331(2010).
RN [32]
RP REVIEW.
RX PubMed=19935766; DOI=10.1038/icb.2009.88;
RA Perera C., McNeil H.P., Geczy C.L.;
RT "S100 Calgranulins in inflammatory arthritis.";
RL Immunol. Cell Biol. 88:41-49(2010).
RN [33]
RP REVIEW.
RX PubMed=20213444; DOI=10.1007/s00726-010-0528-0;
RA Goyette J., Geczy C.L.;
RT "Inflammation-associated S100 proteins: new mechanisms that regulate
RT function.";
RL Amino Acids 41:821-842(2011).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [35]
RP REVIEW.
RX PubMed=22095980; DOI=10.1161/ATVBAHA.111.236927;
RA Averill M.M., Kerkhoff C., Bornfeldt K.E.;
RT "S100A8 and S100A9 in cardiovascular biology and disease.";
RL Arterioscler. Thromb. Vasc. Biol. 32:223-229(2012).
RN [36]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=21487906; DOI=10.1007/s10753-011-9330-8;
RA Koike A., Arai S., Yamada S., Nagae A., Saita N., Itoh H., Uemoto S.,
RA Totani M., Ikemoto M.;
RT "Dynamic mobility of immunological cells expressing S100A8 and S100A9
RT in vivo: a variety of functional roles of the two proteins as
RT regulators in acute inflammatory reaction.";
RL Inflammation 35:409-419(2012).
RN [37]
RP REVIEW.
RX PubMed=22489132; DOI=10.3390/ijms13032893;
RA Vogl T., Gharibyan A.L., Morozova-Roche L.A.;
RT "Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into
RT multifunctional native and amyloid complexes.";
RL Int. J. Mol. Sci. 13:2893-2917(2012).
RN [38]
RP REVIEW.
RX PubMed=21912088; DOI=10.1159/000330095;
RA Srikrishna G.;
RT "S100A8 and S100A9: new insights into their roles in malignancy.";
RL J. Innate Immun. 4:31-40(2012).
RN [39]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CYBA AND CYBB.
RX PubMed=22808130; DOI=10.1371/journal.pone.0040277;
RA Berthier S., Nguyen M.V., Baillet A., Hograindleur M.A., Paclet M.H.,
RA Polack B., Morel F.;
RT "Molecular interface of S100A8 with cytochrome b and NADPH oxidase
RT activation.";
RL PLoS ONE 7:E40277-E40277(2012).
RN [40]
RP FUNCTION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=22363402; DOI=10.1371/journal.pone.0029333;
RA Atallah M., Krispin A., Trahtemberg U., Ben-Hamron S., Grau A.,
RA Verbovetski I., Mevorach D.;
RT "Constitutive neutrophil apoptosis: regulation by cell concentration
RT via S100 A8/9 and the MEK-ERK pathway.";
RL PLoS ONE 7:E29333-E29333(2012).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
RX PubMed=10771424; DOI=10.1107/S0907444900002833;
RA Ishikawa K., Nakagawa A., Tanaka I., Suzuki M., Nishihira J.;
RT "The structure of human MRP8, a member of the S100 calcium-binding
RT protein family, by MAD phasing at 1.9 A resolution.";
RL Acta Crystallogr. D 56:559-566(2000).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH S100A9, SUBUNIT,
RP AND ZINC-BINDING.
RX PubMed=17553524; DOI=10.1016/j.jmb.2007.04.065;
RA Korndoerfer I.P., Brueckner F., Skerra A.;
RT "The crystal structure of the human (S100A8/S100A9)2 heterotetramer,
RT calprotectin, illustrates how conformational changes of interacting
RT alpha-helices can determine specific association of two EF-hand
RT proteins.";
RL J. Mol. Biol. 370:887-898(2007).
CC -!- FUNCTION: S100A8 is a calcium- and zinc-binding protein which
CC plays a prominent role in the regulation of inflammatory processes
CC and immune response. It can induce neutrophil chemotaxis and
CC adhesion. Predominantly found as calprotectin (S100A8/A9) which
CC has a wide plethora of intra- and extracellular functions. The
CC intracellular functions include: facilitating leukocyte
CC arachidonic acid trafficking and metabolism, modulation of the
CC tubulin-dependent cytoskeleton during migration of phagocytes and
CC activation of the neutrophilic NADPH-oxidase. Activates NADPH-
CC oxidase by facilitating the enzyme complex assembly at the cell
CC membrane, transfering arachidonic acid, an essential cofactor, to
CC the enzyme complex and S100A8 contributes to the enzyme assembly
CC by directly binding to NCF2/P67PHOX. The extracellular functions
CC involve proinfammatory, antimicrobial, oxidant-scavenging and
CC apoptosis-inducing activities. Its proinflammatory activity
CC includes recruitment of leukocytes, promotion of cytokine and
CC chemokine production, and regulation of leukocyte adhesion and
CC migration. Acts as an alarmin or a danger associated molecular
CC pattern (DAMP) molecule and stimulates innate immune cells via
CC binding to pattern recognition receptors such as Toll-like
CC receptor 4 (TLR4) and receptor for advanced glycation endproducts
CC (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-
CC kappa-B signaling pathways resulting in the amplification of the
CC proinflammatory cascade. Has antimicrobial activity towards
CC bacteria and fungi and exerts its antimicrobial activity probably
CC via chelation of Zn(2+) which is essential for microbial growth.
CC Can induce cell death via autophagy and apoptosis and this occurs
CC through the cross-talk of mitochondria and lysosomes via reactive
CC oxygen species (ROS) and the process involves BNIP3. Can regulate
CC neutrophil number and apoptosis by an anti-apoptotic effect;
CC regulates cell survival via ITGAM/ITGB and TLR4 and a signaling
CC mechanism involving MEK-ERK. Its role as an oxidant scavenger has
CC a protective role in preventing exaggerated tissue damage by
CC scavenging oxidants. Can act as a potent amplifier of inflammation
CC in autoimmunity as well as in cancer development and tumor spread.
CC -!- SUBUNIT: Homodimer. Preferentially exists as a heterodimer or
CC heterotetramer with S100A9 known as calprotectin (S100A8/A9).
CC S100A8 interacts with AGER, ATP2A2 and with the heterodimeric
CC complex formed by TLR4 and LY96 (By similarity). Calprotectin
CC (S100A8/9) interacts with CEACAM3 and tubulin filaments in a
CC calcium-dependent manner. Heterotetrameric calprotectin
CC (S100A8/A9) interacts with ANXA6 and associates with tubulin
CC filaments in activated monocytes. S100A8 and calprotectin
CC (S100A8/9) interact with NCF2/P67PHOX, RAC1 and RAC2. Calprotectin
CC (S100A8/9) interacts with CYBA and CYBB.
CC -!- INTERACTION:
CC P06702:S100A9; NbExp=3; IntAct=EBI-355281, EBI-1055001;
CC -!- SUBCELLULAR LOCATION: Secreted. Cytoplasm. Cytoplasm,
CC cytoskeleton. Cell membrane; Peripheral membrane protein.
CC Note=Predominantly localized in the cytoplasm. Upon elevation of
CC the intracellular calcium level, translocated from the cytoplasm
CC to the cytoskeleton and the cell membrane. Upon neutrophil
CC activation or endothelial adhesion of monocytes, is secreted via a
CC microtubule-mediated, alternative pathway.
CC -!- TISSUE SPECIFICITY: Calprotectin (S100A8/9) is predominantly
CC expressed in myeloid cells. Except for inflammatory conditions,
CC the expression is restricted to a specific stage of myeloid
CC differentiation since both proteins are expressed in circulating
CC neutrophils and monocytes but are absent in normal tissue
CC macrophages and lymphocytes. Under chronic inflammatory
CC conditions, such as psoriasis and malignant disorders, also
CC expressed in the epidermis. Found in high concentrations at local
CC sites of inflammation or in the serum of patients with
CC inflammatory diseases such as rheumatoid, cystic fibrosis,
CC inflammatory bowel disease, Crohn's disease, giant cell arteritis,
CC cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus,
CC and progressive systemic sclerosis. Involved in the formation and
CC deposition of amyloids in the aging prostate known as corpora
CC amylacea inclusions. Strongly up-regulated in many tumors,
CC including gastric, esophageal, colon, pancreatic, bladder,
CC ovarian, thyroid, breast and skin cancers.
CC -!- MISCELLANEOUS: Binds two calcium ions per molecule with an
CC affinity similar to that of the S100 proteins.
CC -!- SIMILARITY: Belongs to the S-100 family.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/S100A8ID46446ch1q21.html";
CC -----------------------------------------------------------------------
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DR EMBL; Y00278; CAA68390.1; -; mRNA.
DR EMBL; X06234; CAA29580.1; -; mRNA.
DR EMBL; M21005; AAA36327.1; -; Genomic_DNA.
DR EMBL; AK291328; BAF84017.1; -; mRNA.
DR EMBL; CR407674; CAG28602.1; -; mRNA.
DR EMBL; BT007378; AAP36042.1; -; mRNA.
DR EMBL; AL591704; CAI19497.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53330.1; -; Genomic_DNA.
DR EMBL; CH471121; EAW53331.1; -; Genomic_DNA.
DR EMBL; BC005928; AAH05928.1; -; mRNA.
DR PIR; A31848; BCHUCF.
DR RefSeq; NP_002955.2; NM_002964.4.
DR UniGene; Hs.416073; -.
DR PDB; 1MR8; X-ray; 1.90 A; A/B=1-93.
DR PDB; 1XK4; X-ray; 1.80 A; A/B/E/F/I/J=1-93.
DR PDB; 4GGF; X-ray; 1.60 A; A/K/S/U=1-93.
DR PDBsum; 1MR8; -.
DR PDBsum; 1XK4; -.
DR PDBsum; 4GGF; -.
DR ProteinModelPortal; P05109; -.
DR SMR; P05109; 1-90.
DR DIP; DIP-1165N; -.
DR IntAct; P05109; 31.
DR MINT; MINT-1151603; -.
DR STRING; 9606.ENSP00000357721; -.
DR PhosphoSite; P05109; -.
DR DMDM; 115442; -.
DR SWISS-2DPAGE; P05109; -.
DR PaxDb; P05109; -.
DR PeptideAtlas; P05109; -.
DR PRIDE; P05109; -.
DR DNASU; 6279; -.
DR Ensembl; ENST00000368732; ENSP00000357721; ENSG00000143546.
DR Ensembl; ENST00000368733; ENSP00000357722; ENSG00000143546.
DR GeneID; 6279; -.
DR KEGG; hsa:6279; -.
DR UCSC; uc001fbs.3; human.
DR CTD; 6279; -.
DR GeneCards; GC01M153362; -.
DR HGNC; HGNC:10498; S100A8.
DR HPA; CAB002791; -.
DR HPA; HPA024372; -.
DR MIM; 123885; gene.
DR neXtProt; NX_P05109; -.
DR PharmGKB; PA34910; -.
DR eggNOG; NOG39611; -.
DR HOVERGEN; HBG001479; -.
DR InParanoid; P05109; -.
DR OMA; DTWFKEL; -.
DR OrthoDB; EOG76HQ48; -.
DR PhylomeDB; P05109; -.
DR ChiTaRS; S100A8; human.
DR EvolutionaryTrace; P05109; -.
DR GeneWiki; S100_calcium_binding_protein_A8; -.
DR GenomeRNAi; 6279; -.
DR NextBio; 24373; -.
DR PRO; PR:P05109; -.
DR Bgee; P05109; -.
DR CleanEx; HS_S100A8; -.
DR Genevestigator; P05109; -.
DR GO; GO:0005856; C:cytoskeleton; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:UniProtKB.
DR GO; GO:0050544; F:arachidonic acid binding; TAS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; TAS:UniProtKB.
DR GO; GO:0008017; F:microtubule binding; TAS:UniProtKB.
DR GO; GO:0050786; F:RAGE receptor binding; TAS:UniProtKB.
DR GO; GO:0035662; F:Toll-like receptor 4 binding; TAS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; TAS:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0002526; P:acute inflammatory response; IEA:Ensembl.
DR GO; GO:0006914; P:autophagy; IDA:UniProtKB.
DR GO; GO:0032602; P:chemokine production; TAS:UniProtKB.
DR GO; GO:0002544; P:chronic inflammatory response; IEA:Ensembl.
DR GO; GO:0042742; P:defense response to bacterium; TAS:UniProtKB.
DR GO; GO:0050832; P:defense response to fungus; TAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002523; P:leukocyte migration involved in inflammatory response; IDA:UniProtKB.
DR GO; GO:0070488; P:neutrophil aggregation; IDA:UniProtKB.
DR GO; GO:0030593; P:neutrophil chemotaxis; IDA:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; TAS:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:UniProtKB.
DR GO; GO:0051493; P:regulation of cytoskeleton organization; TAS:UniProtKB.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR GO; GO:0032119; P:sequestering of zinc ion; TAS:UniProtKB.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR001751; S100/CaBP-9k_CS.
DR InterPro; IPR013787; S100_Ca-bd_sub.
DR InterPro; IPR028474; S100A8.
DR PANTHER; PTHR11639:SF5; PTHR11639:SF5; 1.
DR Pfam; PF01023; S_100; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
DR PROSITE; PS00303; S100_CABP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antimicrobial; Apoptosis; Autophagy; Calcium;
KW Cell membrane; Chemotaxis; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Immunity; Inflammatory response;
KW Innate immunity; Membrane; Metal-binding; Reference proteome; Repeat;
KW S-nitrosylation; Secreted; Zinc.
FT CHAIN 1 93 Protein S100-A8.
FT /FTId=PRO_0000143993.
FT INIT_MET 1 1 Removed; alternate (By similarity).
FT CHAIN 2 93 Protein S100-A8, N-terminally processed.
FT /FTId=PRO_0000421773.
FT DOMAIN 12 47 EF-hand 1.
FT DOMAIN 46 81 EF-hand 2.
FT CA_BIND 20 33 1; low affinity.
FT CA_BIND 59 70 2; high affinity.
FT METAL 17 17 Zinc (Probable).
FT METAL 27 27 Zinc (Probable).
FT METAL 83 83 Zinc (Probable).
FT METAL 87 87 Zinc (Probable).
FT MOD_RES 42 42 S-nitrosocysteine.
FT MUTAGEN 42 42 C->A: Loss of antifungal activity.
FT CONFLICT 80 93 VAAHKKSHEESHKE -> WQPTKKAMKKATKSS (in
FT Ref. 1; CAA68390).
FT HELIX 4 20
FT STRAND 22 25
FT HELIX 31 41
FT HELIX 44 47
FT HELIX 51 58
FT STRAND 63 66
FT HELIX 68 86
SQ SEQUENCE 93 AA; 10835 MW; 78F589140B9CE166 CRC64;
MLTELEKALN SIIDVYHKYS LIKGNFHAVY RDDLKKLLET ECPQYIRKKG ADVWFKELDI
NTDGAVNFQE FLILVIKMGV AAHKKSHEES HKE
//
MIM
123885
*RECORD*
*FIELD* NO
123885
*FIELD* TI
*123885 S100 CALCIUM-BINDING PROTEIN A8; S100A8
;;CYSTIC FIBROSIS ANTIGEN; CFAG;;
CALGRANULIN A; CAGA; CGLA;;
read moreMYELOID-RELATED PROTEIN 8; MRP8
S100A8/S100A9 COMPLEX, INCLUDED;;
CALPROTECTIN, INCLUDED
*FIELD* TX
DESCRIPTION
Calprotectin, the heterodimeric protein complex composed of S100A8 and
S100A9 (123886), is a major calcium- and zinc-binding protein in the
cytosol of neutrophils, monocytes, and keratinocytes (Sampson et al.,
2002). Vogl et al. (2007) noted that complexes of S100A8 and S100A9 are
the physiologically relevant forms of these proteins.
CLONING
Wilson et al. (1975) found a serum protein abnormality in both
heterozygotes and homozygotes with cystic fibrosis (CF; 219700).
Immunologic quantitation of the protein, called CF antigen, allowed the
3 genotypes to be distinguished (Manson and Brock, 1980; Bullock et al.,
1982).
Van Heyningen et al. (1985) showed that a protein immunologically
indistinguishable from CF antigen is present at high levels in
granulocytes from normal and CF persons as well as in myeloid leukemia
cells. They studied somatic cell hybrids between a mouse myeloid stem
cell line and human myeloid leukemia cells and found that CFAg was
expressed only when human chromosome 1 was present. The authors were
inclined to think that the accumulated protein was itself the product of
the CF gene and that it was altered so that it could not be processed
normally; thus, the site of the mutation might be a region of a
polypeptide chain that acts as a site for a specific proteolytic
cleavage step.
Dorin et al. (1987) isolated cDNA clones for CFA from a library
constructed with mRNA from chronic myeloid leukemia cells. The complete
nucleotide sequence was obtained from the cDNA clone and by primary
extension of mRNA. The amino acid sequence, as predicted from the
nucleotide sequence, showed significant homology with intestinal and
brain calcium-binding proteins. Dorin et al. (1987) concluded that
abnormal accumulation of such a protein in CF should be investigated,
since there is gathering evidence that the basic defect is in pathways
controlling chloride channel activity (Welsh and Liedtke, 1986; Frizzell
et al., 1986).
Wilkinson et al. (1988) produced monoclonal antibodies specifically
recognizing CFAG. Immunoaffinity purification of CFAG from several
sources showed 2 components: one of molecular weight 11,000 and one of
molecular weight 14,000. Wilkinson et al. (1988) isolated cDNA clones
corresponding to each protein. Since the major source of these proteins
is neutrophil granulocytes, Wilkinson et al. (1988) suggested the names
calgranulin A (CAGA) and B (CAGB; 123886). Both CAGA and CAGB show
homology with the calcium-binding protein S100 (S100A1; 176940).
Wilkinson et al. (1988) used the monoclonal antibodies to study tissue
distribution of the 2 proteins. Strong expression was found in
granulocytes and in a restricted subset of normal stratified squamous
epithelium, including tongue, esophagus, and buccal cells. Lung,
pancreas, and skin, sites where the cystic fibrosis defect is expressed,
were not calgranulin-positive. A number of hyperproliferative neoplastic
or frankly malignant epithelia were found to express the 2 proteins.
GENE FUNCTION
Calprotectin is a protein complex consisting of S100A8 and S100A9.
Corbin et al. (2008) found that neutrophil-derived calprotectin
inhibited growth of Staphylococcus aureus in abscesses through chelation
of Mn(2+) and Zn(2+), an activity that resulted in reprogramming of the
bacterial transcriptome. Abscesses of mice lacking calprotectin had
enhanced levels of metals and increased staphylococcal proliferation.
Corbin et al. (2008) concluded that calprotectin is a critical factor in
the innate immune response to infection and that metal chelation is a
mechanism for inhibiting microbial growth inside abscessed tissue.
Vogl et al. (2007) demonstrated that mice lacking Mrp8-Mrp14 (123886)
complexes are protected from endotoxin-induced lethal shock and
Escherichia coli-induced abdominal sepsis. Both proteins are released
during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the
endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the
active component that induces intracellular translocation of myeloid
differentiation primary response protein-88 (MYD88; 602170) and
activation of interleukin-1 receptor-associated kinase-1 (IRAK1; 300283)
and nuclear factor-kappa-B (NFKB; see 164011), resulting in elevated
expression of tumor necrosis factor-alpha (TNF-alpha; 191160). Using
phagocytes expressing a nonfunctional Toll-like receptor-4 (TLR4;
603030), HEK293 cells transfected with TLR4, CD14 (158120), and MD2
(LY96; 605243), and by surface plasmon resonance studies in vitro, Vogl
et al. (2007) demonstrated that MRP8 specifically interacts with the
TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Vogl
et al. (2007) concluded that MRP8-MRP14 complexes are novel inflammatory
components that amplify phagocyte activation during sepsis upstream of
TNF-alpha-dependent effects.
Using a mouse model of autoimmunity, Loser et al. (2010) showed that
production of the damage-associated molecular pattern (DAMP) molecules
Mrp8 and Mrp14 was essential for induction of autoreactive Cd8 (see
186910)-positive T cells and development of systemic autoimmunity. FACS
analysis demonstrated that this effect of Mrp8 and Mrp14 was associated
with Tlr4 signaling and increased Il17 (603149) expression.
Immunohistochemical analysis revealed upregulated MRP8 and MRP14
expression in human cutaneous lupus erythematosus (see 152700) lesions,
and MRP8 and MRP14 were detectable in sera from individuals with active
disease. IL17 was upregulated in CD8-positive T cells from individuals
with lupus when stimulated with MRP8 and MRP14, suggesting that MRP8 and
MRP14 have a key role in the development of autoreactive lymphocytes
during autoimmune disease. Loser et al. (2010) concluded that there is a
link between the local expression of DAMP molecules and systemic
autoimmunity.
MAPPING
Using somatic cell hybrids containing rearranged human chromosomes,
Dorin et al. (1987) localized the CFA gene to 1q12-q22.
Using probes for both subunits of the CF-associated antigen, isolated
from a chronic myeloid leukemia-derived cDNA library, van Heyningen et
al. (1989) and Dorin et al. (1990) confirmed the assignment of CFAG
(CAGA) to 1q12-q21 and showed that CAGB cosegregates with it in a panel
of somatic cell hybrids.
BIOCHEMICAL FEATURES
Psoriasis (see 177900) is an inflammatory skin disorder characterized by
keratinocyte hyperproliferation and altered differentiation. Linkage
analyses have identified at least 7 distinct disease susceptibility
regions. PSORS4 (603935) maps to chromosome 1q21, within the epidermal
differentiation complex (EDC; see 152445), a cluster that contains 13
genes encoding S100 calcium-binding proteins. Semprini et al. (2002)
analyzed S100 gene expression in psoriatic individuals from 2 large
pedigrees characterized by linkage studies, 1 linked and 1 unlinked to
the 1q21 locus. The analyses demonstrated that only the 1q21-linked
family had upregulation of S100A8, S100A9, and, to a lesser extent,
S100A7 (600353) and S100A12 (603112). Later studies confirmed
S100A8/S100A9-specific overexpression in 1q-linked pedigrees.
Zenz et al. (2005) showed that inducible epidermal deletion of JunB
(165161) and its functional companion c-Jun (165160) in adult mice leads
within 2 weeks to a phenotype resembling the histologic and molecular
hallmarks of psoriasis, including arthritic lesions. In contrast to the
skin phenotype, the development of arthritic lesions required T and B
cells and signaling through tumor necrosis factor receptor-1 (TNFR1;
191190). Prior to the disease onset, the chemotactic proteins S100A8 and
S100A9, which map to the psoriasis susceptibility region PSORS4, were
strongly induced in mutant keratinocytes in vivo and in vitro. Zenz et
al. (2005) proposed that the abrogation of JunB/activator protein-1
(AP1) in keratinocytes triggers chemokine/cytokine expression, which
recruits neutrophils and macrophages to the epidermis, thereby
contributing to the phenotypic changes observed in psoriasis. Thus,
their data supported the hypothesis that epidermal alterations are
sufficient to initiate both skin lesions and arthritis in psoriasis.
Calprotectin, the complex of S100A8 and S100A9, is a major calcium- and
zinc-binding protein in the cytosol of neutrophils, monocytes, and
keratinocytes. Although serum concentrations of calprotectin are raised
in many inflammatory conditions, they are generally lower than 10 mg/L.
Sampson et al. (2002) reported greatly elevated serum concentrations in
5 patients with hyperzincemia and hypercalprotectinemia (194470), a
seemingly novel disorder of zinc metabolism. All 5 patients presented
with recurrent infections, hepatosplenomegaly, anemia, and evidence of
systemic inflammation. Cutaneous inflammation was present in 3, and 3
presented in infancy with severe growth failure. As no structural
defects in the S100A8 or S100A9 subunits of calprotectin were detected,
Sampson et al. (2002) suggested that the hypercalprotectinemia was
caused by a defect in its metabolism.
NOMENCLATURE
Schafer et al. (1995) isolated a YAC from 1q21 on which 9 different
genes coding for S100 calcium-binding proteins could be localized. The
clustered organization of S100 genes allowed introduction of a new
logical nomenclature based on their physical arrangement on the
chromosome with S100A1 being closest to the telomere and S100A9 being
closest to the centromere. In the new nomenclature, CAGA became S100A8.
Schafer et al. (1995) commented that S100A8 had been given 9 different
names by groups who had independently studied the same protein.
*FIELD* RF
1. Bullock, S.; Hayward, C.; Manson, J.; Brock, D. J. H.; Raeburn,
J. A.: Quantitative immunoassays for diagnosis and carrier detection
in cystic fibrosis. Clin. Genet. 21: 336-341, 1982.
2. Corbin, B. D.; Seeley, E. H.; Raab, A.; Feldmann, J.; Miller, M.
R.; Torres, V. J.; Anderson, K. L.; Dattilo, B. M.; Dunman, P. M.;
Gerads, R.; Caprioli, R. M.; Nacken, W.; Chazin, W. J.; Skaar, E.
P.: Metal chelation and inhibition of bacterial growth in tissue
abscesses. Science 319: 962-965, 2008.
3. Dorin, J. R.; Emslie, E.; van Heyningen, V.: Related calcium-binding
proteins map to the same subregion of chromosome 1q and to an extended
region of synteny on mouse chromosome 3. Genomics 8: 420-426, 1990.
4. Dorin, J. R.; Novak, M.; Hill, R. E.; Brock, D. J. H.; Secher,
D. S.; van Heyningen, V.: A clue to the basic defect in cystic fibrosis
from cloning the CF antigen gene. Nature 326: 614-617, 1987.
5. Frizzell, R. A.; Rechkemmer, G.; Shoemaker, R. L.: Altered regulation
of airway epithelial cell chloride channels in cystic fibrosis. Science 233:
558-560, 1986.
6. Loser, K.; Vogl, T.; Voskort, M.; Lueken, A.; Kupas, V.; Nacken,
W.; Klenner, L.; Kuhn, A.; Foell, D.; Sorokin, L.; Luger, T. A.; Roth,
J.; Beissert, S.: The Toll-like receptor 4 ligands Mrp8 and Mrp14
are crucial in the development of autoreactive CD8+ T cells. Nature
Med. 16: 713-717, 2010.
7. Manson, J. C.; Brock, D. J. H.: Development of a quantitative
immunoassay for the cystic fibrosis gene. Lancet 315: 330-331, 1980.
Note: Originally Volume I.
8. Sampson, B.; Fagerhol, M. K.; Sunderkotter, C.; Golden, B. E.;
Richmond, P.; Klein, N.; Kovar, I. Z.; Beattie, J. H.; Wolska-Kusnierz,
B.; Saito, Y.; Roth, J.: Hyperzincaemia and hypercalprotectinaemia:
a new disorder of zinc metabolism. Lancet 360: 1742-1745, 2002.
9. Schafer, B. W.; Wicki, R.; Engelkamp, D.; Mattei, M.-G.; Heizmann,
C. W.: Isolation of a YAC clone covering a cluster of nine S100 genes
on human chromosome 1q21: rationale for a new nomenclature of the
S100 calcium-binding protein family. Genomics 25: 638-643, 1995.
10. Semprini, S.; Capon, F.; Tacconelli, A.; Giardina, E.; Orecchia,
A.; Mingarelli, R.; Gobello, T.; Zambruno, G.; Botta, A.; Fabrizi,
G.; Novelli, G.: Evidence for differential S100 gene over-expression
in psoriatic patients from genetically heterogeneous pedigrees. Hum.
Genet. 111: 310-313, 2002.
11. van Heyningen, V.; Emslie, E.; Dorin, J. R.: Related calcium
binding proteins map to the same sub-region of chromosome 1q and to
an extended region of synteny on mouse chromosome 3. (Abstract) Cytogenet.
Cell Genet. 51: 1095, 1989.
12. van Heyningen, V.; Hayward, C.; Fletcher, J.; McAuley, C.: Tissue
localization and chromosomal assignment of a serum protein which tracks
the cystic fibrosis gene. Nature 315: 513-515, 1985.
13. Vogl, T.; Tenbrock, K.; Ludwig, S.; Leukert, N.; Ehrhardt, C.;
van Zoelen, M. A. D.; Nacken, W.; Foell, D.; van der Poll, T.; Sorg,
C.; Roth, J.: Mrp8 and Mrp14 are endogenous activators of Toll-like
receptor 4, promoting lethal, endotoxin-induced shock. Nature Med. 13:
1042-1049, 2007.
14. Welsh, M. J.; Liedtke, C. M.: Chloride and potassium channels
in cystic fibrosis airway epithelia. Nature 322: 467-470, 1986.
15. Wilkinson, M. M.; Busuttil, A.; Hayward, C.; Brock, D. J. H.;
Dorin, J. R.; van Heyningen, V.: Expression pattern of two related
cystic fibrosis-associated calcium-binding proteins in normal and
abnormal tissues. J. Cell Sci. 91: 221-230, 1988.
16. Wilson, G. B.; Fudenberg, H. H.; Jahn, T. L.: Studies on cystic
fibrosis using isoelectric focusing. I. An assay for detection of
cystic fibrosis homozygotes and heterozygote carriers from serum. Pediat.
Res. 9: 635-640, 1975.
17. Zenz, R.; Eferl, R.; Kenner, L.; Florin, L.; Hummerich, L.; Mehic,
D.; Scheuch, H.; Angel, P.; Tschachler, E.; Wagner, E. F.: Psoriasis-like
skin disease and arthritis caused by inducible epidermal deletion
of Jun proteins. Nature 437: 369-375, 2005. Note: Erratum: Nature
440: 708 only, 2006.
*FIELD* CN
Paul J. Converse - updated: 7/6/2010
Ada Hamosh - updated: 3/26/2008
Paul J. Converse - updated: 2/29/2008
Ada Hamosh - updated: 11/3/2005
Victor A. McKusick - updated: 1/29/2003
Victor A. McKusick - updated: 11/13/2002
*FIELD* CD
Victor A. McKusick: 11/28/1990
*FIELD* ED
mgross: 07/08/2010
mgross: 7/8/2010
terry: 7/6/2010
mgross: 2/13/2009
terry: 2/3/2009
alopez: 3/27/2008
terry: 3/26/2008
mgross: 2/29/2008
alopez: 6/5/2006
alopez: 11/4/2005
terry: 11/3/2005
carol: 2/4/2003
tkritzer: 1/29/2003
terry: 1/29/2003
tkritzer: 11/22/2002
tkritzer: 11/15/2002
terry: 11/13/2002
mark: 1/26/1996
mark: 6/15/1995
mimadm: 6/25/1994
carol: 6/24/1994
supermim: 3/16/1992
carol: 3/4/1992
carol: 11/28/1990
*RECORD*
*FIELD* NO
123885
*FIELD* TI
*123885 S100 CALCIUM-BINDING PROTEIN A8; S100A8
;;CYSTIC FIBROSIS ANTIGEN; CFAG;;
CALGRANULIN A; CAGA; CGLA;;
read moreMYELOID-RELATED PROTEIN 8; MRP8
S100A8/S100A9 COMPLEX, INCLUDED;;
CALPROTECTIN, INCLUDED
*FIELD* TX
DESCRIPTION
Calprotectin, the heterodimeric protein complex composed of S100A8 and
S100A9 (123886), is a major calcium- and zinc-binding protein in the
cytosol of neutrophils, monocytes, and keratinocytes (Sampson et al.,
2002). Vogl et al. (2007) noted that complexes of S100A8 and S100A9 are
the physiologically relevant forms of these proteins.
CLONING
Wilson et al. (1975) found a serum protein abnormality in both
heterozygotes and homozygotes with cystic fibrosis (CF; 219700).
Immunologic quantitation of the protein, called CF antigen, allowed the
3 genotypes to be distinguished (Manson and Brock, 1980; Bullock et al.,
1982).
Van Heyningen et al. (1985) showed that a protein immunologically
indistinguishable from CF antigen is present at high levels in
granulocytes from normal and CF persons as well as in myeloid leukemia
cells. They studied somatic cell hybrids between a mouse myeloid stem
cell line and human myeloid leukemia cells and found that CFAg was
expressed only when human chromosome 1 was present. The authors were
inclined to think that the accumulated protein was itself the product of
the CF gene and that it was altered so that it could not be processed
normally; thus, the site of the mutation might be a region of a
polypeptide chain that acts as a site for a specific proteolytic
cleavage step.
Dorin et al. (1987) isolated cDNA clones for CFA from a library
constructed with mRNA from chronic myeloid leukemia cells. The complete
nucleotide sequence was obtained from the cDNA clone and by primary
extension of mRNA. The amino acid sequence, as predicted from the
nucleotide sequence, showed significant homology with intestinal and
brain calcium-binding proteins. Dorin et al. (1987) concluded that
abnormal accumulation of such a protein in CF should be investigated,
since there is gathering evidence that the basic defect is in pathways
controlling chloride channel activity (Welsh and Liedtke, 1986; Frizzell
et al., 1986).
Wilkinson et al. (1988) produced monoclonal antibodies specifically
recognizing CFAG. Immunoaffinity purification of CFAG from several
sources showed 2 components: one of molecular weight 11,000 and one of
molecular weight 14,000. Wilkinson et al. (1988) isolated cDNA clones
corresponding to each protein. Since the major source of these proteins
is neutrophil granulocytes, Wilkinson et al. (1988) suggested the names
calgranulin A (CAGA) and B (CAGB; 123886). Both CAGA and CAGB show
homology with the calcium-binding protein S100 (S100A1; 176940).
Wilkinson et al. (1988) used the monoclonal antibodies to study tissue
distribution of the 2 proteins. Strong expression was found in
granulocytes and in a restricted subset of normal stratified squamous
epithelium, including tongue, esophagus, and buccal cells. Lung,
pancreas, and skin, sites where the cystic fibrosis defect is expressed,
were not calgranulin-positive. A number of hyperproliferative neoplastic
or frankly malignant epithelia were found to express the 2 proteins.
GENE FUNCTION
Calprotectin is a protein complex consisting of S100A8 and S100A9.
Corbin et al. (2008) found that neutrophil-derived calprotectin
inhibited growth of Staphylococcus aureus in abscesses through chelation
of Mn(2+) and Zn(2+), an activity that resulted in reprogramming of the
bacterial transcriptome. Abscesses of mice lacking calprotectin had
enhanced levels of metals and increased staphylococcal proliferation.
Corbin et al. (2008) concluded that calprotectin is a critical factor in
the innate immune response to infection and that metal chelation is a
mechanism for inhibiting microbial growth inside abscessed tissue.
Vogl et al. (2007) demonstrated that mice lacking Mrp8-Mrp14 (123886)
complexes are protected from endotoxin-induced lethal shock and
Escherichia coli-induced abdominal sepsis. Both proteins are released
during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the
endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the
active component that induces intracellular translocation of myeloid
differentiation primary response protein-88 (MYD88; 602170) and
activation of interleukin-1 receptor-associated kinase-1 (IRAK1; 300283)
and nuclear factor-kappa-B (NFKB; see 164011), resulting in elevated
expression of tumor necrosis factor-alpha (TNF-alpha; 191160). Using
phagocytes expressing a nonfunctional Toll-like receptor-4 (TLR4;
603030), HEK293 cells transfected with TLR4, CD14 (158120), and MD2
(LY96; 605243), and by surface plasmon resonance studies in vitro, Vogl
et al. (2007) demonstrated that MRP8 specifically interacts with the
TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Vogl
et al. (2007) concluded that MRP8-MRP14 complexes are novel inflammatory
components that amplify phagocyte activation during sepsis upstream of
TNF-alpha-dependent effects.
Using a mouse model of autoimmunity, Loser et al. (2010) showed that
production of the damage-associated molecular pattern (DAMP) molecules
Mrp8 and Mrp14 was essential for induction of autoreactive Cd8 (see
186910)-positive T cells and development of systemic autoimmunity. FACS
analysis demonstrated that this effect of Mrp8 and Mrp14 was associated
with Tlr4 signaling and increased Il17 (603149) expression.
Immunohistochemical analysis revealed upregulated MRP8 and MRP14
expression in human cutaneous lupus erythematosus (see 152700) lesions,
and MRP8 and MRP14 were detectable in sera from individuals with active
disease. IL17 was upregulated in CD8-positive T cells from individuals
with lupus when stimulated with MRP8 and MRP14, suggesting that MRP8 and
MRP14 have a key role in the development of autoreactive lymphocytes
during autoimmune disease. Loser et al. (2010) concluded that there is a
link between the local expression of DAMP molecules and systemic
autoimmunity.
MAPPING
Using somatic cell hybrids containing rearranged human chromosomes,
Dorin et al. (1987) localized the CFA gene to 1q12-q22.
Using probes for both subunits of the CF-associated antigen, isolated
from a chronic myeloid leukemia-derived cDNA library, van Heyningen et
al. (1989) and Dorin et al. (1990) confirmed the assignment of CFAG
(CAGA) to 1q12-q21 and showed that CAGB cosegregates with it in a panel
of somatic cell hybrids.
BIOCHEMICAL FEATURES
Psoriasis (see 177900) is an inflammatory skin disorder characterized by
keratinocyte hyperproliferation and altered differentiation. Linkage
analyses have identified at least 7 distinct disease susceptibility
regions. PSORS4 (603935) maps to chromosome 1q21, within the epidermal
differentiation complex (EDC; see 152445), a cluster that contains 13
genes encoding S100 calcium-binding proteins. Semprini et al. (2002)
analyzed S100 gene expression in psoriatic individuals from 2 large
pedigrees characterized by linkage studies, 1 linked and 1 unlinked to
the 1q21 locus. The analyses demonstrated that only the 1q21-linked
family had upregulation of S100A8, S100A9, and, to a lesser extent,
S100A7 (600353) and S100A12 (603112). Later studies confirmed
S100A8/S100A9-specific overexpression in 1q-linked pedigrees.
Zenz et al. (2005) showed that inducible epidermal deletion of JunB
(165161) and its functional companion c-Jun (165160) in adult mice leads
within 2 weeks to a phenotype resembling the histologic and molecular
hallmarks of psoriasis, including arthritic lesions. In contrast to the
skin phenotype, the development of arthritic lesions required T and B
cells and signaling through tumor necrosis factor receptor-1 (TNFR1;
191190). Prior to the disease onset, the chemotactic proteins S100A8 and
S100A9, which map to the psoriasis susceptibility region PSORS4, were
strongly induced in mutant keratinocytes in vivo and in vitro. Zenz et
al. (2005) proposed that the abrogation of JunB/activator protein-1
(AP1) in keratinocytes triggers chemokine/cytokine expression, which
recruits neutrophils and macrophages to the epidermis, thereby
contributing to the phenotypic changes observed in psoriasis. Thus,
their data supported the hypothesis that epidermal alterations are
sufficient to initiate both skin lesions and arthritis in psoriasis.
Calprotectin, the complex of S100A8 and S100A9, is a major calcium- and
zinc-binding protein in the cytosol of neutrophils, monocytes, and
keratinocytes. Although serum concentrations of calprotectin are raised
in many inflammatory conditions, they are generally lower than 10 mg/L.
Sampson et al. (2002) reported greatly elevated serum concentrations in
5 patients with hyperzincemia and hypercalprotectinemia (194470), a
seemingly novel disorder of zinc metabolism. All 5 patients presented
with recurrent infections, hepatosplenomegaly, anemia, and evidence of
systemic inflammation. Cutaneous inflammation was present in 3, and 3
presented in infancy with severe growth failure. As no structural
defects in the S100A8 or S100A9 subunits of calprotectin were detected,
Sampson et al. (2002) suggested that the hypercalprotectinemia was
caused by a defect in its metabolism.
NOMENCLATURE
Schafer et al. (1995) isolated a YAC from 1q21 on which 9 different
genes coding for S100 calcium-binding proteins could be localized. The
clustered organization of S100 genes allowed introduction of a new
logical nomenclature based on their physical arrangement on the
chromosome with S100A1 being closest to the telomere and S100A9 being
closest to the centromere. In the new nomenclature, CAGA became S100A8.
Schafer et al. (1995) commented that S100A8 had been given 9 different
names by groups who had independently studied the same protein.
*FIELD* RF
1. Bullock, S.; Hayward, C.; Manson, J.; Brock, D. J. H.; Raeburn,
J. A.: Quantitative immunoassays for diagnosis and carrier detection
in cystic fibrosis. Clin. Genet. 21: 336-341, 1982.
2. Corbin, B. D.; Seeley, E. H.; Raab, A.; Feldmann, J.; Miller, M.
R.; Torres, V. J.; Anderson, K. L.; Dattilo, B. M.; Dunman, P. M.;
Gerads, R.; Caprioli, R. M.; Nacken, W.; Chazin, W. J.; Skaar, E.
P.: Metal chelation and inhibition of bacterial growth in tissue
abscesses. Science 319: 962-965, 2008.
3. Dorin, J. R.; Emslie, E.; van Heyningen, V.: Related calcium-binding
proteins map to the same subregion of chromosome 1q and to an extended
region of synteny on mouse chromosome 3. Genomics 8: 420-426, 1990.
4. Dorin, J. R.; Novak, M.; Hill, R. E.; Brock, D. J. H.; Secher,
D. S.; van Heyningen, V.: A clue to the basic defect in cystic fibrosis
from cloning the CF antigen gene. Nature 326: 614-617, 1987.
5. Frizzell, R. A.; Rechkemmer, G.; Shoemaker, R. L.: Altered regulation
of airway epithelial cell chloride channels in cystic fibrosis. Science 233:
558-560, 1986.
6. Loser, K.; Vogl, T.; Voskort, M.; Lueken, A.; Kupas, V.; Nacken,
W.; Klenner, L.; Kuhn, A.; Foell, D.; Sorokin, L.; Luger, T. A.; Roth,
J.; Beissert, S.: The Toll-like receptor 4 ligands Mrp8 and Mrp14
are crucial in the development of autoreactive CD8+ T cells. Nature
Med. 16: 713-717, 2010.
7. Manson, J. C.; Brock, D. J. H.: Development of a quantitative
immunoassay for the cystic fibrosis gene. Lancet 315: 330-331, 1980.
Note: Originally Volume I.
8. Sampson, B.; Fagerhol, M. K.; Sunderkotter, C.; Golden, B. E.;
Richmond, P.; Klein, N.; Kovar, I. Z.; Beattie, J. H.; Wolska-Kusnierz,
B.; Saito, Y.; Roth, J.: Hyperzincaemia and hypercalprotectinaemia:
a new disorder of zinc metabolism. Lancet 360: 1742-1745, 2002.
9. Schafer, B. W.; Wicki, R.; Engelkamp, D.; Mattei, M.-G.; Heizmann,
C. W.: Isolation of a YAC clone covering a cluster of nine S100 genes
on human chromosome 1q21: rationale for a new nomenclature of the
S100 calcium-binding protein family. Genomics 25: 638-643, 1995.
10. Semprini, S.; Capon, F.; Tacconelli, A.; Giardina, E.; Orecchia,
A.; Mingarelli, R.; Gobello, T.; Zambruno, G.; Botta, A.; Fabrizi,
G.; Novelli, G.: Evidence for differential S100 gene over-expression
in psoriatic patients from genetically heterogeneous pedigrees. Hum.
Genet. 111: 310-313, 2002.
11. van Heyningen, V.; Emslie, E.; Dorin, J. R.: Related calcium
binding proteins map to the same sub-region of chromosome 1q and to
an extended region of synteny on mouse chromosome 3. (Abstract) Cytogenet.
Cell Genet. 51: 1095, 1989.
12. van Heyningen, V.; Hayward, C.; Fletcher, J.; McAuley, C.: Tissue
localization and chromosomal assignment of a serum protein which tracks
the cystic fibrosis gene. Nature 315: 513-515, 1985.
13. Vogl, T.; Tenbrock, K.; Ludwig, S.; Leukert, N.; Ehrhardt, C.;
van Zoelen, M. A. D.; Nacken, W.; Foell, D.; van der Poll, T.; Sorg,
C.; Roth, J.: Mrp8 and Mrp14 are endogenous activators of Toll-like
receptor 4, promoting lethal, endotoxin-induced shock. Nature Med. 13:
1042-1049, 2007.
14. Welsh, M. J.; Liedtke, C. M.: Chloride and potassium channels
in cystic fibrosis airway epithelia. Nature 322: 467-470, 1986.
15. Wilkinson, M. M.; Busuttil, A.; Hayward, C.; Brock, D. J. H.;
Dorin, J. R.; van Heyningen, V.: Expression pattern of two related
cystic fibrosis-associated calcium-binding proteins in normal and
abnormal tissues. J. Cell Sci. 91: 221-230, 1988.
16. Wilson, G. B.; Fudenberg, H. H.; Jahn, T. L.: Studies on cystic
fibrosis using isoelectric focusing. I. An assay for detection of
cystic fibrosis homozygotes and heterozygote carriers from serum. Pediat.
Res. 9: 635-640, 1975.
17. Zenz, R.; Eferl, R.; Kenner, L.; Florin, L.; Hummerich, L.; Mehic,
D.; Scheuch, H.; Angel, P.; Tschachler, E.; Wagner, E. F.: Psoriasis-like
skin disease and arthritis caused by inducible epidermal deletion
of Jun proteins. Nature 437: 369-375, 2005. Note: Erratum: Nature
440: 708 only, 2006.
*FIELD* CN
Paul J. Converse - updated: 7/6/2010
Ada Hamosh - updated: 3/26/2008
Paul J. Converse - updated: 2/29/2008
Ada Hamosh - updated: 11/3/2005
Victor A. McKusick - updated: 1/29/2003
Victor A. McKusick - updated: 11/13/2002
*FIELD* CD
Victor A. McKusick: 11/28/1990
*FIELD* ED
mgross: 07/08/2010
mgross: 7/8/2010
terry: 7/6/2010
mgross: 2/13/2009
terry: 2/3/2009
alopez: 3/27/2008
terry: 3/26/2008
mgross: 2/29/2008
alopez: 6/5/2006
alopez: 11/4/2005
terry: 11/3/2005
carol: 2/4/2003
tkritzer: 1/29/2003
terry: 1/29/2003
tkritzer: 11/22/2002
tkritzer: 11/15/2002
terry: 11/13/2002
mark: 1/26/1996
mark: 6/15/1995
mimadm: 6/25/1994
carol: 6/24/1994
supermim: 3/16/1992
carol: 3/4/1992
carol: 11/28/1990