RBCC Red Blood Cell Collection

LTF (GIG12, LF) [Confidence: high (present in two of the MS resources)]
Lactotransferrin; Lactoferrin; 3.4.21.- (Growth-inhibiting protein 12; Talalactoferrin; Lactoferricin-H; Lfcin-H; Kaliocin-1; Lactoferroxin-A; Lactoferroxin-B; Lactoferroxin-C; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00298860
IPI00298860 Lactotransferrin precursor Lactotransferrin precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 5 n/a n/a extracellular binds RBC n/a found at its expected molecular weight found at molecular weight

UniProt P02788
ID TRFL_HUMAN Reviewed; 710 AA.
AC P02788; B2MV13; B7Z4X2; E7EQH5; O00756; Q16780; Q16785; Q16786;
read moreAC Q16789; Q5DSM0; Q8IU92; Q8IZH6; Q8TCD2; Q96KZ4; Q96KZ5; Q9H1Z3;
AC Q9UCY5;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 24-JAN-2006, sequence version 6.
DT 22-JAN-2014, entry version 177.
DE RecName: Full=Lactotransferrin;
DE Short=Lactoferrin;
DE EC=3.4.21.-;
DE AltName: Full=Growth-inhibiting protein 12;
DE AltName: Full=Talalactoferrin;
DE Contains:
DE RecName: Full=Lactoferricin-H;
DE Short=Lfcin-H;
DE Contains:
DE RecName: Full=Kaliocin-1;
DE Contains:
DE RecName: Full=Lactoferroxin-A;
DE Contains:
DE RecName: Full=Lactoferroxin-B;
DE Contains:
DE RecName: Full=Lactoferroxin-C;
DE Flags: Precursor;
GN Name=LTF; Synonyms=GIG12, LF;
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] (ISOFORM 1), AND VARIANTS ARG-22 INS;
RP THR-148 AND CYS-422.
RC TISSUE=Mammary gland;
RX PubMed=2402455; DOI=10.1093/nar/18.17.5288;
RA Rey M.W., Woloshuk S.L., de Boer H.A., Pieper F.R.;
RT "Complete nucleotide sequence of human mammary gland lactoferrin.";
RL Nucleic Acids Res. 18:5288-5288(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-22 INS.
RC TISSUE=Mammary gland;
RA Cho Y.Y.;
RT "Cloning of human lactoferrin gene and its polymorphism in normal and
RT cancer cells.";
RL Thesis (1994), Genetic Engineering Research Institute, South Korea.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND DELTALF), ALTERNATIVE
RP SPLICING, AND TISSUE SPECIFICITY.
RC TISSUE=Lung;
RX PubMed=9122171; DOI=10.1073/pnas.94.6.2198;
RA Siebert P.D., Huang B.C.;
RT "Identification of an alternative form of human lactoferrin mRNA that
RT is expressed differentially in normal tissues and tumor-derived cell
RT lines.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:2198-2203(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ARG-22 INS;
RP THR-29; ARG-47 AND ASP-579.
RC TISSUE=Mammary gland;
RX PubMed=11702692;
RA Cheng H., Chen X.Z., Huan L.D.;
RT "cDNA cloning and sequence analysis of human lactoferrin.";
RL Sheng Wu Gong Cheng Xue Bao 17:385-387(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), X-RAY CRYSTALLOGRAPHY (3.40
RP ANGSTROMS) OF 22-710 IN COMPLEX WITH IRON AND CARBONATE, AND VARIANTS
RP ARG-22 INS; THR-29; ARG-47 AND ASP-579.
RC TISSUE=Seminal vesicle;
RX PubMed=22900286;
RA Kumar J., Weber W., Munchau S., Yadav S., Singh S.B., Saravanan K.,
RA Paramasivam M., Sharma S., Kaur P., Bhushan A., Srinivasan A.,
RA Betzel C., Singh T.P.;
RT "Crystal structure of human seminal diferric lactoferrin at 3.4
RT Angstrom resolution.";
RL Indian J. Biochem. Biophys. 40:14-21(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 20-30,
RP FUNCTION, AND VARIANTS ARG-22 INS; THR-29 AND ARG-47.
RC TISSUE=Blood;
RX PubMed=14573629; DOI=10.1128/IAI.71.11.6141-6147.2003;
RA Velliyagounder K., Kaplan J.B., Furgang D., Legarda D., Diamond G.,
RA Parkin R.E., Fine D.H.;
RT "One of two human lactoferrin variants exhibits increased
RT antibacterial and transcriptional activation activities and is
RT associated with localized juvenile periodontitis.";
RL Infect. Immun. 71:6141-6147(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Bone marrow;
RA Wei X., Han J., Rado T.A.;
RT "Human neutrophil lactoferrin coding and 5' flanking region DNA
RT sequences.";
RL Submitted (FEB-1992) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ARG-22 INS;
RP THR-29 AND ARG-47.
RC TISSUE=Prostate;
RA Conneely O.M.;
RL Submitted (MAY-1992) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ARG-22 INS;
RP THR-29; ARG-47 AND ASP-579.
RC TISSUE=Mammary gland;
RA Shi Y.-Q., Zhang Y., Zheng Y.-M.;
RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ARG-22 INS AND
RP CYS-422.
RA Kim J.W.;
RT "Identification of a growth inhibition gene.";
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-22 INS; THR-29 AND
RP ARG-47.
RA Allayous C., Marianne-Pepin T.;
RT "Mutations in ELA2 and LTF genes.";
RL Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM DELTALF).
RC TISSUE=Lung;
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 [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-22
RP INS.
RC TISSUE=Prostate;
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 [15]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-15.
RX PubMed=1480183; DOI=10.1210/me.6.11.1969;
RA Teng C.T., Liu Y., Yang N., Walmer D., Panella T.;
RT "Differential molecular mechanism of the estrogen action that
RT regulates lactoferrin gene in human and mouse.";
RL Mol. Endocrinol. 6:1969-1981(1992).
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-710 (ISOFORM 1), AND VARIANT ARG-22
RP INS.
RC TISSUE=Mammary gland;
RX PubMed=2374734; DOI=10.1093/nar/18.13.4013;
RA Powell M.J., Ogden J.E.;
RT "Nucleotide sequence of human lactoferrin cDNA.";
RL Nucleic Acids Res. 18:4013-4013(1990).
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-710 (ISOFORM 1), AND VARIANT ARG-22
RP INS.
RC TISSUE=Mammary gland;
RA Liang Q., Jimenez-Flores R., Richardson T.;
RT "Molecular cloning and sequence analysis of human lactoferrin.";
RL Submitted (DEC-1991) to the EMBL/GenBank/DDBJ databases.
RN [18]
RP PROTEIN SEQUENCE OF 20-710 (ISOFORM 1), AND DISULFIDE BONDS.
RX PubMed=6510420; DOI=10.1111/j.1432-1033.1984.tb08607.x;
RA Metz-Boutigue M.-H., Jolles J., Mazurier J., Schoentgen F.,
RA Legrand D., Spik G., Montreuil J., Jolles P.;
RT "Human lactotransferrin: amino acid sequence and structural
RT comparisons with other transferrins.";
RL Eur. J. Biochem. 145:659-676(1984).
RN [19]
RP PRELIMINARY PROTEIN SEQUENCE OF 20-72; 133-170; 256-277; 359-528 AND
RP 608-663 (ISOFORM 1).
RX PubMed=6794640; DOI=10.1016/0005-2795(81)90016-7;
RA Metz-Boutigue M.-H., Mazurier J., Jolles J., Spik G., Montreuil J.,
RA Jolles P.;
RT "The present state of the human lactotransferrin sequence. Study and
RT alignment of the cyanogen bromide fragments and characterization of N-
RT and C-terminal domains.";
RL Biochim. Biophys. Acta 670:243-254(1981).
RN [20]
RP PROTEIN SEQUENCE OF 20-65 (ISOFORM 1), IDENTIFICATION OF LACTOFERRICIN
RP PEPTIDE, FUNCTION, AND SYNTHESIS OF 36-58.
RC TISSUE=Milk;
RX PubMed=1599934; DOI=10.1016/0167-4838(92)90346-F;
RA Bellamy W., Takase M., Yamauchi K., Wakabayashi H., Kawase K.,
RA Tomita M.;
RT "Identification of the bactericidal domain of lactoferrin.";
RL Biochim. Biophys. Acta 1121:130-136(1992).
RN [21]
RP PROTEIN SEQUENCE OF 20-40 (ISOFORM 1), FUNCTION, GLYCOSAMINOGLYCAN
RP BINDING, AND SYNTHESIS OF 20-51; 20-45 AND 25-51.
RC TISSUE=Milk;
RX PubMed=8089135;
RA Mann D.M., Romm E., Migliorini M.;
RT "Delineation of the glycosaminoglycan-binding site in the human
RT inflammatory response protein lactoferrin.";
RL J. Biol. Chem. 269:23661-23667(1994).
RN [22]
RP PROTEIN SEQUENCE OF 20-56 (ISOFORM 1).
RC TISSUE=Seminal plasma;
RX PubMed=8551695;
RA Sato I.;
RT "Characterization of the 84-kDa protein with ABH activity in human
RT seminal plasma.";
RL Nihon Hoigaku Zasshi 49:281-293(1995).
RN [23]
RP PROTEIN SEQUENCE OF 24-32; 38-43; 50-57 AND 59-67 (ISOFORM 1),
RP STRUCTURE BY NMR OF 20-67 (LACTOFERRICIN), MASS SPECTROMETRY, AND
RP DISULFIDE BONDS.
RC TISSUE=Milk;
RX PubMed=16048952; DOI=10.1128/AAC.49.8.3387-3395.2005;
RA Hunter H.N., Demcoe A.R., Jenssen H., Gutteberg T.J., Vogel H.J.;
RT "Human lactoferricin is partially folded in aqueous solution and is
RT better stabilized in a membrane mimetic solvent.";
RL Antimicrob. Agents Chemother. 49:3387-3395(2005).
RN [24]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 236-710, AND VARIANT ASP-579.
RA McCombie W.R., Wilson R., Chen E., Gibbs R., Zuo L., Johnson D.,
RA Nhan M., Parnell L., Dedhia N., Ansari A., Mardis E., Schutz K.,
RA Gnoj L., la Bastide M., Kaplan N., Greco T., Touchman J., Muzny D.,
RA Chen C.N., Evans C., Fitzgerald M., See L.H., Tang M., Porcel B.M.,
RA Dragan Y., Giacalone J., Pae A., Powell E., Solinsky K.A., Desilva U.,
RA Diaz-Perez S., Zhou X., Yu Y., Watanabe M., Doggett N., Garcia D.,
RA Sagripanti J.L.;
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [25]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 435-710.
RC TISSUE=Myeloid;
RX PubMed=3477300;
RA Rado T.A., Wei X., Benz E.J. Jr.;
RT "Isolation of lactoferrin cDNA from a human myeloid library and
RT expression of mRNA during normal and leukemic myelopoiesis.";
RL Blood 70:989-993(1987).
RN [26]
RP PROTEIN SEQUENCE OF 608-710.
RX PubMed=7049727; DOI=10.1016/0014-5793(82)80229-9;
RA Metz-Boutigue M.-H., Jolles J., Mazurier J., Spik G., Montreuil J.,
RA Jolles P.;
RT "An 88 amino acid long C-terminal sequence of human
RT lactotransferrin.";
RL FEBS Lett. 142:107-110(1982).
RN [27]
RP FUNCTION.
RX PubMed=6802759;
RA Arnold R.R., Russell J.E., Champion W.J., Brewer M., Gauthier J.J.;
RT "Bactericidal activity of human lactoferrin: differentiation from the
RT stasis of iron deprivation.";
RL Infect. Immun. 35:792-799(1982).
RN [28]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=2981589;
RA Cramer E., Pryzwansky K.B., Villeval J.L., Testa U., Breton-Gorius J.;
RT "Ultrastructural localization of lactoferrin and myeloperoxidase in
RT human neutrophils by immunogold.";
RL Blood 65:423-432(1985).
RN [29]
RP FUNCTION.
RX PubMed=3169987;
RA Ellison R.T. III, Giehl T.J., LaForce F.M.;
RT "Damage of the outer membrane of enteric gram-negative bacteria by
RT lactoferrin and transferrin.";
RL Infect. Immun. 56:2774-2781(1988).
RN [30]
RP CHARACTERIZATION OF LACTOFERROXINS.
RX PubMed=1369293;
RA Tani F., Iio K., Chiba H., Yoshikawa M.;
RT "Isolation and characterization of opioid antagonist peptides derived
RT from human lactoferrin.";
RL Agric. Biol. Chem. 54:1803-1810(1990).
RN [31]
RP FUNCTION, AND MUTAGENESIS OF 20-G--R-23.
RX PubMed=9359845;
RA van Berkel P.H., Geerts M.E., van Veen H.A., Mericskay M.,
RA de Boer H.A., Nuijens J.H.;
RT "N-terminal stretch Arg2, Arg3, Arg4 and Arg5 of human lactoferrin is
RT essential for binding to heparin, bacterial lipopolysaccharide, human
RT lysozyme and DNA.";
RL Biochem. J. 328:145-151(1997).
RN [32]
RP FUNCTION.
RX PubMed=11083624; DOI=10.1128/AAC.44.12.3257-3263.2000;
RA Lupetti A., Paulusma-Annema A., Welling M.M., Senesi S.,
RA van Dissel J.T., Nibbering P.H.;
RT "Candidacidal activities of human lactoferrin peptides derived from
RT the N terminus.";
RL Antimicrob. Agents Chemother. 44:3257-3263(2000).
RN [33]
RP TISSUE SPECIFICITY.
RX PubMed=10792619; DOI=10.1046/j.1523-1755.2000.00050.x;
RA Abrink M., Larsson E., Gobl A., Hellman L.;
RT "Expression of lactoferrin in the kidney: implications for innate
RT immunity and iron metabolism.";
RL Kidney Int. 57:2004-2010(2000).
RN [34]
RP FUNCTION, SYNTHESIS OF 20-29 AND 39-49, AND MUTAGENESIS OF
RP 20-GLY--ARG-22.
RX PubMed=11179314; DOI=10.1128/IAI.69.3.1469-1476.2001;
RA Nibbering P.H., Ravensbergen E., Welling M.M., van Berkel L.A.,
RA van Berkel P.H., Pauwels E.K., Nuijens J.H.;
RT "Human lactoferrin and peptides derived from its N terminus are highly
RT effective against infections with antibiotic-resistant bacteria.";
RL Infect. Immun. 69:1469-1476(2001).
RN [35]
RP FUNCTION.
RX PubMed=12037568; DOI=10.1038/417552a;
RA Singh P.K., Parsek M.R., Greenberg E.P., Welsh M.J.;
RT "A component of innate immunity prevents bacterial biofilm
RT development.";
RL Nature 417:552-555(2002).
RN [36]
RP SUBCELLULAR LOCATION, AND ALTERNATIVE PROMOTER USAGE.
RX PubMed=12565886; DOI=10.1016/S0006-291X(02)03077-2;
RA Liu D., Wang X., Zhang Z., Teng C.T.;
RT "An intronic alternative promoter of the human lactoferrin gene is
RT activated by Ets.";
RL Biochem. Biophys. Res. Commun. 301:472-479(2003).
RN [37]
RP FUNCTION, AND SYNTHESIS OF 36-58 AND 171-201 (KALIOCIN-1).
RX PubMed=12693969; DOI=10.1023/A:1022657630698;
RA Viejo-Diaz M., Andres M.T., Perez-Gil J., Sanchez M., Fierro J.F.;
RT "Potassium efflux induced by a new lactoferrin-derived peptide
RT mimicking the effect of native human lactoferrin on the bacterial
RT cytoplasmic membrane.";
RL Biochemistry (Mosc.) 68:217-227(2003).
RN [38]
RP FUNCTION AS A PROTEASE, AND MUTAGENESIS OF LYS-92; PRO-270 AND
RP SER-278.
RX PubMed=12535064; DOI=10.1046/j.1365-2958.2003.03327.x;
RA Hendrixson D.R., Qiu J., Shewry S.C., Fink D.L., Petty S., Baker E.N.,
RA Plaut A.G., St Geme J.W. III;
RT "Human milk lactoferrin is a serine protease that cleaves Haemophilus
RT surface proteins at arginine-rich sites.";
RL Mol. Microbiol. 47:607-617(2003).
RN [39]
RP FUNCTION, AND SUBCELLULAR LOCATION (DELTALF).
RX PubMed=15222485; DOI=10.1023/B:BIOM.0000027712.81056.13;
RA Breton M., Mariller C., Benaissa M., Caillaux K., Browaeys E.,
RA Masson M., Vilain J.P., Mazurier J., Pierce A.;
RT "Expression of delta-lactoferrin induces cell cycle arrest.";
RL BioMetals 17:325-329(2004).
RN [40]
RP FUNCTION.
RX PubMed=15166119; DOI=10.1210/en.2003-1307;
RA Cornish J., Callon K.E., Naot D., Palmano K.P., Banovic T., Bava U.,
RA Watson M., Lin J.M., Tong P.C., Chen Q., Chan V.A., Reid H.E.,
RA Fazzalari N., Baker H.M., Baker E.N., Haggarty N.W., Grey A.B.,
RA Reid I.R.;
RT "Lactoferrin is a potent regulator of bone cell activity and increases
RT bone formation in vivo.";
RL Endocrinology 145:4366-4374(2004).
RN [41]
RP FUNCTION.
RX PubMed=16842782; DOI=10.1016/j.febslet.2006.06.091;
RA Kim C.W., Son K.N., Choi S.Y., Kim J.;
RT "Human lactoferrin upregulates expression of KDR/Flk-1 and stimulates
RT VEGF-A-mediated endothelial cell proliferation and migration.";
RL FEBS Lett. 580:4332-4336(2006).
RN [42]
RP FUNCTION.
RX PubMed=17481742; DOI=10.1016/j.antiviral.2007.03.012;
RA Mistry N., Drobni P., Naslund J., Sunkari V.G., Jenssen H.,
RA Evander M.;
RT "The anti-papillomavirus activity of human and bovine lactoferricin.";
RL Antiviral Res. 75:258-265(2007).
RN [43]
RP IDENTIFICATION IN A COMPLEX WITH CLU; SEMG1 AND EPPIN.
RX PubMed=17567961; DOI=10.1095/biolreprod.107.060194;
RA Wang Z., Widgren E.E., Richardson R.T., O'Rand M.G.;
RT "Characterization of an eppin protein complex from human semen and
RT spermatozoa.";
RL Biol. Reprod. 77:476-484(2007).
RN [44]
RP FUNCTION.
RX PubMed=17079302; DOI=10.1128/JVI.01995-06;
RA Johansson C., Jonsson M., Marttila M., Persson D., Fan X.L., Skog J.,
RA Frangsmyr L., Wadell G., Arnberg N.;
RT "Adenoviruses use lactoferrin as a bridge for CAR-independent binding
RT to and infection of epithelial cells.";
RL J. Virol. 81:954-963(2007).
RN [45]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156; ASN-497 AND ASN-642,
RP AND MASS SPECTROMETRY.
RC TISSUE=Milk;
RX PubMed=18780401; DOI=10.1002/pmic.200701057;
RA Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.;
RT "Identification of N-linked glycoproteins in human milk by hydrophilic
RT interaction liquid chromatography and mass spectrometry.";
RL Proteomics 8:3833-3847(2008).
RN [46]
RP FUNCTION.
RX PubMed=19033648; DOI=10.1172/JCI36226;
RA Bournazou I., Pound J.D., Duffin R., Bournazos S., Melville L.A.,
RA Brown S.B., Rossi A.G., Gregory C.D.;
RT "Apoptotic human cells inhibit migration of granulocytes via release
RT of lactoferrin.";
RL J. Clin. Invest. 119:20-32(2009).
RN [47]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-497, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [48]
RP FUNCTION, AND PTM.
RX PubMed=20345905; DOI=10.1111/j.1742-4658.2010.07620.x;
RA Ando K., Hasegawa K., Shindo K., Furusawa T., Fujino T., Kikugawa K.,
RA Nakano H., Takeuchi O., Akira S., Akiyama T., Gohda J., Inoue J.,
RA Hayakawa M.;
RT "Human lactoferrin activates NF-kappaB through the Toll-like receptor
RT 4 pathway while it interferes with the lipopolysaccharide-stimulated
RT TLR4 signaling.";
RL FEBS J. 277:2051-2066(2010).
RN [49]
RP GLYCOSYLATION, PHOSPHORYLATION, AND UBIQUITINATION (ISOFORM DELTALF).
RX PubMed=20404350; DOI=10.1074/jbc.M109.080572;
RA Hardiville S., Hoedt E., Mariller C., Benaissa M., Pierce A.;
RT "O-GlcNAcylation/phosphorylation cycling at Ser10 controls both
RT transcriptional activity and stability of delta-lactoferrin.";
RL J. Biol. Chem. 285:19205-19218(2010).
RN [50]
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 [51]
RP FUNCTION AS A TRANSCRIPTION FACTOR (ISOFORM DELTALF), AND DNA-BINDING
RP (ISOFORM DELTALF).
RX PubMed=22320386; DOI=10.1139/o11-070;
RA Mariller C., Hardiville S., Hoedt E., Huvent I., Pina-Canseco S.,
RA Pierce A.;
RT "Delta-lactoferrin, an intracellular lactoferrin isoform that acts as
RT a transcription factor.";
RL Biochem. Cell Biol. 90:307-319(2012).
RN [52]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS), AND SEQUENCE REVISION.
RX PubMed=2585506; DOI=10.1016/0022-2836(89)90602-5;
RA Anderson B.F., Baker H.M., Norris G.E., Rice D.W., Baker E.N.;
RT "Structure of human lactoferrin: crystallographic structure analysis
RT and refinement at 2.8-A resolution.";
RL J. Mol. Biol. 209:711-734(1989).
RN [53]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 20-710.
RX PubMed=1772635; DOI=10.1107/S0108768191008418;
RA Norris G.E., Anderson B.F., Baker E.N.;
RT "Molecular replacement solution of the structure of apolactoferrin, a
RT protein displaying large-scale conformational change.";
RL Acta Crystallogr. B 47:998-1004(1991).
RN [54]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 20-710 IN COMPLEX WITH
RP COPPER AND CARBONATE, AND GLYCOSYLATION AT ASN-156 AND ASN-497.
RX PubMed=1581307; DOI=10.1021/bi00133a020;
RA Smith C.A., Anderson B.F., Baker H.M., Baker E.N.;
RT "Metal substitution in transferrins: the crystal structure of human
RT copper-lactoferrin at 2.1-A resolution.";
RL Biochemistry 31:4527-4533(1992).
RN [55]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 21-352 IN COMPLEX WITH IRON
RP AND CARBONATE, AND DISULFIDE BONDS.
RX PubMed=8371268; DOI=10.1006/jmbi.1993.1462;
RA Day C.L., Anderson B.F., Tweedie J.W., Baker E.N.;
RT "Structure of the recombinant N-terminal lobe of human lactoferrin at
RT 2.0 A resolution.";
RL J. Mol. Biol. 232:1084-1100(1993).
RN [56]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 20-710 IN COMPLEX WITH
RP COPPER AND OXALATE, AND GLYCOSYLATION AT ASN-156.
RX PubMed=15299444; DOI=10.1107/S0907444994000491;
RA Smith C.A., Anderson B.F., Baker H.M., Baker E.N.;
RT "Structure of copper- and oxalate-substituted human lactoferrin at 2.0
RT A resolution.";
RL Acta Crystallogr. D 50:302-316(1994).
RN [57]
RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 110-268, AND GLYCOSYLATION
RP AT ASN-156.
RX PubMed=8069634; DOI=10.1016/S0969-2126(00)00022-8;
RA Bourne Y., Mazurier J., Legrand D., Rouge P., Montreuil J., Spik G.,
RA Cambillau C.;
RT "Structures of a legume lectin complexed with the human
RT lactotransferrin N2 fragment, and with an isolated biantennary
RT glycopeptide: role of the fucose moiety.";
RL Structure 2:209-219(1994).
RN [58]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 20-710 IN COMPLEX WITH IRON
RP AND CARBONATE, AND GLYCOSYLATION AT ASN-156 AND ASN-497.
RX PubMed=15299793; DOI=10.1107/S0907444994013521;
RA Haridas M., Anderson B.F., Baker E.N.;
RT "Structure of human diferric lactoferrin refined at 2.2-A
RT resolution.";
RL Acta Crystallogr. D 51:629-646(1995).
RN [59]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 20-710 IN COMPLEX WITH IRON
RP AND OXALATE.
RX PubMed=8703903; DOI=10.1021/bi960288y;
RA Baker H.M., Anderson B.F., Brodie A.M., Shongwe M.S., Smith C.A.,
RA Baker E.N.;
RT "Anion binding by transferrins: importance of second-shell effects
RT revealed by the crystal structure of oxalate-substituted diferric
RT lactoferrin.";
RL Biochemistry 35:9007-9013(1996).
RN [60]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 22-352 OF MUTANTS GLU-140
RP AND SER-140 IN COMPLEX WITH IRON AND CARBONATE, AND MUTAGENESIS OF
RP ARG-140.
RX PubMed=8931543; DOI=10.1021/bi961729g;
RA Faber H.R., Baker C.J., Day C.L., Tweedie J.W., Baker E.N.;
RT "Mutation of arginine 121 in lactoferrin destabilizes iron binding by
RT disruption of anion binding: crystal structures of R121S and R121E
RT mutants.";
RL Biochemistry 35:14473-14479(1996).
RN [61]
RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 21-352 OF MUTANT SER-79 IN
RP COMPLEX WITH IRON AND CARBONATE, AND MUTAGENESIS OF ASP-79.
RX PubMed=8594202; DOI=10.1006/jmbi.1996.0091;
RA Faber H.R., Bland T., Day C.L., Norris G.E., Tweedie J.W., Baker E.N.;
RT "Altered domain closure and iron binding in transferrins: the crystal
RT structure of the Asp60Ser mutant of the amino-terminal half-molecule
RT of human lactoferrin.";
RL J. Mol. Biol. 256:352-363(1996).
RN [62]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 21-353 OF MUTANT MET-272 IN
RP COMPLEX WITH IRON AND CARBONATE, AND MUTAGENESIS OF HIS-272.
RX PubMed=9003186; DOI=10.1021/bi961908y;
RA Nicholson H., Anderson B.F., Bland T., Shewry S.C., Tweedie J.W.,
RA Baker E.N.;
RT "Mutagenesis of the histidine ligand in human lactoferrin: iron
RT binding properties and crystal structure of the histidine-
RT 253-->methionine mutant.";
RL Biochemistry 36:341-346(1997).
RN [63]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 20-710.
RX PubMed=10089508; DOI=10.1107/S0907444998004417;
RA Jameson G.B., Anderson B.F., Norris G.E., Thomas D.H., Baker E.N.;
RT "Structure of human apolactoferrin at 2.0 A resolution. Refinement and
RT analysis of ligand-induced conformational change.";
RL Acta Crystallogr. D 54:1319-1335(1998).
RN [64]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) 20-710 IN COMPLEX WITH IRON AND
RP CARBONATE.
RX PubMed=10089347; DOI=10.1107/S0907444998011226;
RA Sun X.L., Baker H.M., Shewry S.C., Jameson G.B., Baker E.N.;
RT "Structure of recombinant human lactoferrin expressed in Aspergillus
RT awamori.";
RL Acta Crystallogr. D 55:403-407(1999).
RN [65]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 21-348 OF MUTANT LYS-229 IN
RP COMPLEX WITH IRON AND CARBONATE, AND MUTAGENESIS OF ARG-229.
RX PubMed=10828980; DOI=10.1021/bi0001224;
RA Peterson N.A., Anderson B.F., Jameson G.B., Tweedie J.W., Baker E.N.;
RT "Crystal structure and iron-binding properties of the R210K mutant of
RT the N-lobe of human lactoferrin: implications for iron release from
RT transferrins.";
RL Biochemistry 39:6625-6633(2000).
RN [66]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 21-710 IN COMPLEX WITH
RP CERIUM AND CARBONATE.
RX PubMed=11128996; DOI=10.1007/s007750000157;
RA Baker H.M., Baker C.J., Smith C.A., Baker E.N.;
RT "Metal substitution in transferrins: specific binding of cerium(IV)
RT revealed by the crystal structure of cerium-substituted human
RT lactoferrin.";
RL J. Biol. Inorg. Chem. 5:692-698(2000).
RN [67]
RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) OF 21-351 OF MUTANT ASP-140,
RP AND MUTAGENESIS OF ARG-140.
RX PubMed=12037297; DOI=10.1107/S0907444902005127;
RA Jameson G.B., Anderson B.F., Breyer W.A., Day C.L., Tweedie J.W.,
RA Baker E.N.;
RT "Structure of a domain-opened mutant (R121D) of the human lactoferrin
RT N-lobe refined from a merohedrally twinned crystal form.";
RL Acta Crystallogr. D 58:955-962(2002).
RN [68]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 21-352 OF MUTANTS GLY-229;
RP GLU-229 AND LEU-229 IN COMPLEX WITH IRON AND CARBONATE, AND
RP MUTAGENESIS OF ARG-229.
RX PubMed=12450380; DOI=10.1021/bi020443a;
RA Peterson N.A., Arcus V.L., Anderson B.F., Tweedie J.W., Jameson G.B.,
RA Baker E.N.;
RT "'Dilysine trigger' in transferrins probed by mutagenesis of
RT lactoferrin: crystal structures of the R210G, R210E, and R210L mutants
RT of human lactoferrin.";
RL Biochemistry 41:14167-14175(2002).
RN [69]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 20-710 IN COMPLEX WITH IRON
RP AND CARBONATE, AND GLYCOSYLATION AT ASN-156 AND ASN-497.
RA Vikram P., Prem Kumar R., Singh N., Kumar J., Ethayathulla A.S.,
RA Sharma S., Kaur P., Singh T.P.;
RT "Structure of human diferric lactoferrin at 2.5A resolution using
RT crystals grown at pH 6.5.";
RL Submitted (MAR-2004) to the PDB data bank.
RN [70]
RP STRUCTURE BY NMR OF 39-49 IN COMPLEX WITH LIPOPOLYSACCHARIDE, AND
RP SYNTHESIS OF 39-49.
RX PubMed=15687491; DOI=10.1074/jbc.M500266200;
RA Japelj B., Pristovsek P., Majerle A., Jerala R.;
RT "Structural origin of endotoxin neutralization and antimicrobial
RT activity of a lactoferrin-based peptide.";
RL J. Biol. Chem. 280:16955-16961(2005).
RN [71]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 20-710 IN COMPLEX WITH IRON
RP AND CARBONATE, GLYCOSYLATION AT ASN-156 AND ASN-497, AND VARIANT
RP ASP-579.
RX PubMed=16201406; DOI=10.1007/s11248-005-3233-0;
RA Thomassen E.A., van Veen H.A., van Berkel P.H., Nuijens J.H.,
RA Abrahams J.P.;
RT "The protein structure of recombinant human lactoferrin produced in
RT the milk of transgenic cows closely matches the structure of human
RT milk-derived lactoferrin.";
RL Transgenic Res. 14:397-405(2005).
RN [72]
RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) OF 528-535 IN COMPLEX WITH
RP PROTEINASE K.
RA Singh A.K., Singh N., Sharma S., Bhushan A., Singh T.P.;
RT "Crystal structure of the complex formed between proteinase K and a
RT human lactoferrin fragment at 2.9 A resolution.";
RL Submitted (MAY-2006) to the PDB data bank.
RN [73]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 528-535 IN COMPLEX WITH
RP PROTEINASE K.
RA Prem Kumar R., Singh A.K., Singh N., Kaur P., Sharma S., Singh T.P.;
RT "Crystal structure of proteinase K inhibited by a lactoferrin
RT octapeptide Gly-Asp-Glu-Gln-Gly-Glu-Asn-Lys at 2.15 A resolution.";
RL Submitted (JUN-2006) to the PDB data bank.
RN [74]
RP STRUCTURE BY NMR OF 39-49.
RX PubMed=17263370; DOI=10.1021/ja067419v;
RA Japelj B., Zorko M., Majerle A., Pristovsek P., Sanchez-Gomez S.,
RA Martinez de Tejada G., Moriyon I., Blondelle S.E., Brandenburg K.,
RA Andra J., Lohner K., Jerala R.;
RT "The acyl group as the central element of the structural organization
RT of antimicrobial lipopeptide.";
RL J. Am. Chem. Soc. 129:1022-1023(2007).
RN [75]
RP X-RAY CRYSTALLOGRAPHY (2.91 ANGSTROMS) OF 21-362 IN COMPLEX WITH
RP PNEUMOCOCCAL SURFACE PROTEIN A FRAGMENT; IRON AND CARBONATE.
RX PubMed=17543335; DOI=10.1016/j.jmb.2007.04.075;
RA Senkovich O., Cook W.J., Mirza S., Hollingshead S.K.,
RA Protasevich I.I., Briles D.E., Chattopadhyay D.;
RT "Structure of a complex of human lactoferrin N-lobe with pneumococcal
RT surface protein a provides insight into microbial defense mechanism.";
RL J. Mol. Biol. 370:701-713(2007).
RN [76]
RP VARIANTS THR-29 AND ARG-47.
RX PubMed=9873069;
RA Klintworth G.K., Sommer J.R., Obrian G., Han L., Ahmed M.N.,
RA Qumsiyeh M.B., Lin P.-Y., Basti S., Reddy M.K., Kanai A., Hotta Y.,
RA Sugar J., Kumaramanickavel G., Munier F., Schorderet D.F.,
RA El Matri L., Iwata F., Kaiser-Kupfer M., Nagata M., Nakayasu K.,
RA Hejtmancik J.F., Teng C.T.;
RT "Familial subepithelial corneal amyloidosis (gelatinous drop-like
RT corneal dystrophy): exclusion of linkage to lactoferrin gene.";
RL Mol. Vis. 4:31-32(1998).
RN [77]
RP VARIANTS ARG-22 INS AND ARG-47.
RX PubMed=22406253; DOI=10.1016/j.humimm.2012.02.014;
RA Videm V., Dahl H., Walberg L.E., Wiseth R.;
RT "Functional polymorphisms in the LTF gene and risk of coronary artery
RT stenosis.";
RL Hum. Immunol. 73:554-559(2012).
CC -!- FUNCTION: Transferrins are iron binding transport proteins which
CC can bind two Fe(3+) ions in association with the binding of an
CC anion, usually bicarbonate.
CC -!- FUNCTION: Lactotransferrin is a major iron-binding and
CC multifunctional protein found in exocrine fluids such as breast
CC milk and mucosal secretions. Has antimicrobial activity, which
CC depends on the extracellular cation concentration. Antimicrobial
CC properties include bacteriostasis, which is related to its ability
CC to sequester free iron and thus inhibit microbial growth, as well
CC as direct bactericidal properties leading to the release of
CC lipopolysaccharides from the bacterial outer membrane. Can also
CC prevent bacterial biofilm development in P.aeruginosa infection.
CC Has weak antifungal activity against C.albicans. Has anabolic,
CC differentiating and anti-apoptotic effects on osteoblasts and can
CC also inhibit osteoclastogenesis, possibly playing a role in the
CC regulation of bone growth. Promotes binding of species C
CC adenoviruses to epithelial cells, promoting adenovirus infection.
CC Can inhibit papillomavirus infections. Stimulates the TLR4
CC signaling pathway leading to NF-kappa-B activation and subsequent
CC pro-inflammatory cytokine production while also interfering with
CC the lipopolysaccharide (LPS)-stimulated TLR4 signaling. Inhibits
CC neutrophil granulocyte migration to sites of apoptosis, when
CC secreted by apoptotic cells. Stimulates VEGFA-mediated endothelial
CC cell migration and proliferation. Binds heparin, chondroitin
CC sulfate and possibly other glycosaminoglycans (GAGs). Also binds
CC specifically to pneumococcal surface protein A (pspA), the lipid A
CC portion of bacterial lipopolysaccharide (LPS), lysozyme and DNA.
CC -!- FUNCTION: Lactoferricin binds to the bacterial surface and is
CC crucial for the bactericidal functions. Has some antiviral
CC activity against papillomavirus infection. N-terminal region shows
CC strong antifungal activity against C.albicans. Contains two BBXB
CC heparin-binding consensus sequences that appear to form the
CC predominate functional GAG-binding site.
CC -!- FUNCTION: Kaliocin-1 has antimicrobial activity and is able to
CC permeabilize different ions through liposomal membranes.
CC -!- FUNCTION: Lactoferroxins A, B and C have opioid antagonist
CC activity. Lactoferroxin A shows preference for mu-receptors, while
CC lactoferroxin B and C have somewhat higher degrees of preference
CC for kappa-receptors than for mu-receptors.
CC -!- FUNCTION: The lactotransferrin transferrin-like domain 1 functions
CC as a serine protease of the peptidase S60 family that cuts
CC arginine rich regions. This function contributes to the
CC antimicrobial activity.
CC -!- FUNCTION: Isoform DeltaLf: transcription factor with
CC antiproliferative properties and ability to induce cell cycle
CC arrest. Binds to the DeltaLf response element found in the SKP1,
CC BAX, DCPS, and SELH promoters.
CC -!- CATALYTIC ACTIVITY: Preferential at -Arg-Ser-Arg-Arg-|- and -Arg-
CC Arg-Ser-Arg-|-, and of Z-Phe-Arg-|-aminomethylcoumarin.
CC -!- SUBUNIT: Monomer. Found in a complex with LTF, CLU, EPPIN and
CC SEMG1.
CC -!- INTERACTION:
CC P62157:CALM (xeno); NbExp=2; IntAct=EBI-1058602, EBI-397403;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Secreted. Cytoplasmic granule.
CC Note=Secreted into most exocrine fluids by various endothelial
CC cells. Stored in the secondary granules of neutrophils.
CC -!- SUBCELLULAR LOCATION: Isoform DeltaLf: Cytoplasm. Nucleus.
CC Note=Mainly localized in the cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage; Named isoforms=2;
CC Name=1;
CC IsoId=P02788-1; Sequence=Displayed;
CC Name=DeltaLf; Synonyms=Delta-lactoferrin;
CC IsoId=P02788-2; Sequence=VSP_044308;
CC Note=Phosphorylated at Ser-10. Glycosylated at Ser-10.
CC O-GlcNAcylation at Ser-10 inhibits DNA binding and negatively
CC regulates DeltaLf transcriptional activity, whereas
CC phosphorylation activates it. Phosphorylation at Ser-10 also
CC promotes proteasomal degradation;
CC -!- TISSUE SPECIFICITY: High levels are found in saliva and tears,
CC intermediate levels in serum and plasma, and low levels in urine.
CC In kidney, detected in the distal collecting tubules in the
CC medulla but not in the cortical region or in blood vessels.
CC Detected in peripheral blood neutrophils (at protein level).
CC Isoform 1 and isoform DeltaLf are expressed in breast, prostate,
CC spleen, pancreas, kidney, small intestine, lung, skeletal muscle,
CC uterus, thymus and fetal liver. Isoform 1 is expressed in brain,
CC testis and peripheral blood leukocytes; isoform DeltaLf is barely
CC detectable in these tissues. Isoform DeltaLf is expressed in
CC placenta, liver and ovary; isoform 1 is barely detectable in these
CC tissues. In kidney, isoform 1 is expressed at high levels in the
CC collecting tubules of the medulla but at very low levels in the
CC cortex.
CC -!- PTM: Isoform DeltaLf: Ubiquitinated at Lys-379 and Lys-391.
CC -!- PTM: Poly-N-acetyllactosaminic carbohydrate moiety seems to be
CC needed for TLR4 activation.
CC -!- MASS SPECTROMETRY: Mass=5737.8; Method=Electrospray; Range=20-67;
CC Source=PubMed:16048952;
CC -!- POLYMORPHISM: The sequence shown corresponds to the reference
CC genome sequence and is likely to represent the minor allele,
CC whereas most publications refer to the longer sequence containing
CC variant Arg-22 ins. Insertion of the additional arginine in
CC variant Arg-22 ins creates an N-terminal basic cluster of four
CC arginines, all of which appear to be important for the full
CC functionality of the protein, including bactericidal and
CC antifungal activities as well as binding to glycosaminoglycans,
CC pspA, LPS, lysozyme and DNA.
CC -!- SIMILARITY: Belongs to the transferrin family.
CC -!- SIMILARITY: Contains 2 transferrin-like domains.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Lactotransferrin entry;
CC URL="http://en.wikipedia.org/wiki/Lactotransferrin";
CC -----------------------------------------------------------------------
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DR EMBL; X53961; CAA37914.1; -; mRNA.
DR EMBL; U07643; AAB60324.1; -; mRNA.
DR EMBL; AF332168; AAG48753.1; -; mRNA.
DR EMBL; AY178998; AAN75578.2; -; mRNA.
DR EMBL; AY137470; AAN11304.1; -; mRNA.
DR EMBL; M73700; AAA59479.1; -; Genomic_DNA.
DR EMBL; M93150; AAA36159.1; -; mRNA.
DR EMBL; AY165046; AAN63998.1; -; mRNA.
DR EMBL; AY493417; AAS72878.1; -; mRNA.
DR EMBL; EU622050; ACC95966.1; -; Genomic_DNA.
DR EMBL; AK298035; BAH12708.1; -; mRNA.
DR EMBL; AC098613; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC015822; AAH15822.1; -; mRNA.
DR EMBL; BC015823; AAH15823.1; -; mRNA.
DR EMBL; BC022347; AAH22347.1; -; mRNA.
DR EMBL; S52659; AAB24877.1; -; Genomic_DNA.
DR EMBL; X52941; CAA37116.1; -; mRNA.
DR EMBL; M83202; AAA59511.1; -; mRNA.
DR EMBL; M83205; AAA58656.1; -; mRNA.
DR EMBL; U95626; AAB57795.1; -; Genomic_DNA.
DR EMBL; M18642; AAA86665.1; -; mRNA.
DR PIR; G01394; TFHUL.
DR RefSeq; NP_001186078.1; NM_001199149.1.
DR RefSeq; NP_002334.2; NM_002343.3.
DR UniGene; Hs.529517; -.
DR PDB; 1B0L; X-ray; 2.20 A; A=20-710.
DR PDB; 1BKA; X-ray; 2.40 A; A=20-710.
DR PDB; 1CB6; X-ray; 2.00 A; A=20-710.
DR PDB; 1DSN; X-ray; 2.05 A; A=21-352.
DR PDB; 1EH3; X-ray; 2.00 A; A=21-348.
DR PDB; 1FCK; X-ray; 2.20 A; A=21-710.
DR PDB; 1H43; X-ray; 2.20 A; A=21-352.
DR PDB; 1H44; X-ray; 2.00 A; A=21-352.
DR PDB; 1H45; X-ray; 1.95 A; A=21-352.
DR PDB; 1HSE; X-ray; 2.20 A; A=21-353.
DR PDB; 1L5T; X-ray; 3.00 A; A/B=21-351.
DR PDB; 1LCF; X-ray; 2.00 A; A=20-710.
DR PDB; 1LCT; X-ray; 2.00 A; A=21-352.
DR PDB; 1LFG; X-ray; 2.20 A; A=20-710.
DR PDB; 1LFH; X-ray; 2.80 A; A=20-710.
DR PDB; 1LFI; X-ray; 2.10 A; A=20-710.
DR PDB; 1LGB; X-ray; 3.30 A; C=110-268.
DR PDB; 1N76; X-ray; 3.40 A; A=21-710.
DR PDB; 1SQY; X-ray; 2.50 A; A=20-710.
DR PDB; 1U62; NMR; -; A=39-49.
DR PDB; 1VFD; X-ray; 2.50 A; A=22-349.
DR PDB; 1VFE; X-ray; 2.30 A; A=22-352.
DR PDB; 1XV4; NMR; -; A=39-49.
DR PDB; 1XV7; NMR; -; A=39-49.
DR PDB; 1Z6V; NMR; -; A=21-67.
DR PDB; 1Z6W; NMR; -; A=21-67.
DR PDB; 2BJJ; X-ray; 2.40 A; X=21-710.
DR PDB; 2DP4; X-ray; 2.90 A; I=528-535.
DR PDB; 2GMC; NMR; -; A=39-49.
DR PDB; 2GMD; NMR; -; A=39-49.
DR PDB; 2HD4; X-ray; 2.15 A; B=528-535.
DR PDB; 2PMS; X-ray; 2.91 A; A/B=21-362.
DR PDBsum; 1B0L; -.
DR PDBsum; 1BKA; -.
DR PDBsum; 1CB6; -.
DR PDBsum; 1DSN; -.
DR PDBsum; 1EH3; -.
DR PDBsum; 1FCK; -.
DR PDBsum; 1H43; -.
DR PDBsum; 1H44; -.
DR PDBsum; 1H45; -.
DR PDBsum; 1HSE; -.
DR PDBsum; 1L5T; -.
DR PDBsum; 1LCF; -.
DR PDBsum; 1LCT; -.
DR PDBsum; 1LFG; -.
DR PDBsum; 1LFH; -.
DR PDBsum; 1LFI; -.
DR PDBsum; 1LGB; -.
DR PDBsum; 1N76; -.
DR PDBsum; 1SQY; -.
DR PDBsum; 1U62; -.
DR PDBsum; 1VFD; -.
DR PDBsum; 1VFE; -.
DR PDBsum; 1XV4; -.
DR PDBsum; 1XV7; -.
DR PDBsum; 1Z6V; -.
DR PDBsum; 1Z6W; -.
DR PDBsum; 2BJJ; -.
DR PDBsum; 2DP4; -.
DR PDBsum; 2GMC; -.
DR PDBsum; 2GMD; -.
DR PDBsum; 2HD4; -.
DR PDBsum; 2PMS; -.
DR DisProt; DP00616; -.
DR ProteinModelPortal; P02788; -.
DR SMR; P02788; 20-710.
DR DIP; DIP-41354N; -.
DR IntAct; P02788; 7.
DR MINT; MINT-1511753; -.
DR DrugBank; DB00487; Pefloxacin.
DR Allergome; 1384; Hom s LF.
DR MEROPS; S60.001; -.
DR PhosphoSite; P02788; -.
DR UniCarbKB; P02788; -.
DR DMDM; 85700158; -.
DR PaxDb; P02788; -.
DR PRIDE; P02788; -.
DR DNASU; 4057; -.
DR Ensembl; ENST00000231751; ENSP00000231751; ENSG00000012223.
DR Ensembl; ENST00000426532; ENSP00000405719; ENSG00000012223.
DR GeneID; 4057; -.
DR KEGG; hsa:4057; -.
DR UCSC; uc003cpq.3; human.
DR CTD; 4057; -.
DR GeneCards; GC03M046477; -.
DR HGNC; HGNC:6720; LTF.
DR HPA; CAB008645; -.
DR MIM; 150210; gene.
DR MIM; 245480; phenotype.
DR neXtProt; NX_P02788; -.
DR PharmGKB; PA30482; -.
DR eggNOG; NOG87503; -.
DR HOVERGEN; HBG000055; -.
DR InParanoid; P02788; -.
DR KO; K17283; -.
DR OMA; RPVEGYL; -.
DR OrthoDB; EOG7D59N7; -.
DR PhylomeDB; P02788; -.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; LTF; human.
DR EvolutionaryTrace; P02788; -.
DR GeneWiki; Lactoferrin; -.
DR GenomeRNAi; 4057; -.
DR NextBio; 15896; -.
DR PRO; PR:P02788; -.
DR ArrayExpress; P02788; -.
DR Bgee; P02788; -.
DR Genevestigator; P02788; -.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0097013; C:phagocytic vesicle lumen; TAS:Reactome.
DR GO; GO:0030141; C:secretory granule; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0008199; F:ferric iron binding; IEA:InterPro.
DR GO; GO:0008201; F:heparin binding; IDA:MGI.
DR GO; GO:0005506; F:iron ion binding; IDA:UniProtKB.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0019732; P:antifungal humoral response; IDA:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; IEA:UniProtKB-KW.
DR GO; GO:0002227; P:innate immune response in mucosa; IDA:UniProtKB.
DR GO; GO:0033214; P:iron assimilation by chelation and transport; TAS:Reactome.
DR GO; GO:0006826; P:iron ion transport; IEA:InterPro.
DR GO; GO:0031665; P:negative regulation of lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:1900229; P:negative regulation of single-species biofilm formation in or on host organism; IDA:UniProtKB.
DR GO; GO:0001503; P:ossification; IEA:UniProtKB-KW.
DR GO; GO:0090382; P:phagosome maturation; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IDA:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0034145; P:positive regulation of toll-like receptor 4 signaling pathway; IMP:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0032680; P:regulation of tumor necrosis factor production; IDA:UniProtKB.
DR GO; GO:0052572; P:response to host immune response; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR InterPro; IPR016357; Transferrin.
DR InterPro; IPR001156; Transferrin_fam.
DR InterPro; IPR018195; Transferrin_Fe_BS.
DR Pfam; PF00405; Transferrin; 2.
DR PIRSF; PIRSF002549; Transferrin; 1.
DR PRINTS; PR00422; TRANSFERRIN.
DR SMART; SM00094; TR_FER; 2.
DR PROSITE; PS00205; TRANSFERRIN_LIKE_1; 2.
DR PROSITE; PS00206; TRANSFERRIN_LIKE_2; 2.
DR PROSITE; PS00207; TRANSFERRIN_LIKE_3; 2.
DR PROSITE; PS51408; TRANSFERRIN_LIKE_4; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative promoter usage; Antibiotic; Antimicrobial;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disulfide bond; DNA-binding; Glycoprotein; Heparin-binding; Hydrolase;
KW Immunity; Ion transport; Iron; Iron transport; Metal-binding; Nucleus;
KW Osteogenesis; Phosphoprotein; Polymorphism; Protease;
KW Reference proteome; Repeat; Secreted; Serine protease; Signal;
KW Transcription; Transcription regulation; Transport; Ubl conjugation.
FT SIGNAL 1 19
FT CHAIN 20 710 Lactotransferrin.
FT /FTId=PRO_0000035732.
FT PEPTIDE 20 67 Lactoferricin-H.
FT /FTId=PRO_0000422770.
FT PEPTIDE 171 201 Kaliocin-1.
FT /FTId=PRO_0000035733.
FT PEPTIDE 338 343 Lactoferroxin-A.
FT /FTId=PRO_0000035734.
FT PEPTIDE 543 547 Lactoferroxin-B.
FT /FTId=PRO_0000035735.
FT PEPTIDE 680 686 Lactoferroxin-C.
FT /FTId=PRO_0000035736.
FT DOMAIN 25 352 Transferrin-like 1.
FT DOMAIN 364 695 Transferrin-like 2.
FT REGION 20 29 Bactericidal and antifungal activity.
FT REGION 20 24 Critical for glycosaminoglycan, lipid A,
FT lysozyme and DNA binding.
FT REGION 21 22 Important for full bactericidal and
FT antifungal activities.
FT REGION 39 49 Bactericidal and antifungal activity.
FT REGION 39 49 Interaction with lipopolysaccharide.
FT REGION 39 46 Interaction with pspA.
FT REGION 46 51 Involved in glycosaminoglycan binding.
FT REGION 57 58 Interaction with pspA.
FT ACT_SITE 92 92 Probable.
FT ACT_SITE 278 278 Nucleophile (Probable).
FT METAL 79 79 Iron or copper 1.
FT METAL 111 111 Iron or copper 1.
FT METAL 211 211 Iron or copper 1.
FT METAL 272 272 Iron or copper 1; via tele nitrogen.
FT METAL 414 414 Iron or copper 2.
FT METAL 454 454 Iron or copper 2.
FT METAL 547 547 Iron or copper 2.
FT METAL 616 616 Iron or copper 2; via tele nitrogen.
FT BINDING 23 23 PspA.
FT BINDING 32 32 PspA.
FT BINDING 136 136 Carbonate or oxalate 1.
FT BINDING 140 140 Carbonate or oxalate 1.
FT BINDING 142 142 Carbonate or oxalate 1; via amide
FT nitrogen.
FT BINDING 143 143 Carbonate or oxalate 1; via amide
FT nitrogen.
FT BINDING 480 480 Carbonate or oxalate 2.
FT BINDING 484 484 Carbonate or oxalate 2.
FT BINDING 486 486 Carbonate or oxalate 2; via amide
FT nitrogen.
FT BINDING 487 487 Carbonate or oxalate 2; via amide
FT nitrogen.
FT SITE 229 229 Important for iron binding.
FT CARBOHYD 156 156 N-linked (GlcNAc...).
FT CARBOHYD 497 497 N-linked (GlcNAc...).
FT CARBOHYD 642 642 N-linked (GlcNAc...).
FT DISULFID 28 64
FT DISULFID 38 55
FT DISULFID 134 217
FT DISULFID 176 192
FT DISULFID 189 200
FT DISULFID 250 264
FT DISULFID 367 399
FT DISULFID 377 390
FT DISULFID 424 705
FT DISULFID 446 668
FT DISULFID 478 553
FT DISULFID 502 696
FT DISULFID 512 526
FT DISULFID 523 536
FT DISULFID 594 608
FT DISULFID 646 651
FT VAR_SEQ 1 44 Missing (in isoform DeltaLf).
FT /FTId=VSP_044308.
FT VARIANT 22 22 R -> RR (associated with lower plasma
FT lactoferrin concentrations;
FT dbSNP:rs10662431).
FT /FTId=VAR_069298.
FT VARIANT 29 29 A -> T (in dbSNP:rs1126477).
FT /FTId=VAR_013504.
FT VARIANT 47 47 K -> R (decreased antibacterial activity
FT against Gram-positive bacteria; seems to
FT reduce susceptibility to localized
FT juvenile periodontitis; associated with
FT increased plasma lactoferrin
FT concentrations and possibly with
FT susceptibility to coronary artery
FT stenosis; dbSNP:rs1126478).
FT /FTId=VAR_013505.
FT VARIANT 148 148 I -> T (in dbSNP:rs1126479).
FT /FTId=VAR_013506.
FT VARIANT 422 422 G -> C (in dbSNP:rs1042055).
FT /FTId=VAR_013507.
FT VARIANT 579 579 E -> D (in dbSNP:rs2073495).
FT /FTId=VAR_013508.
FT MUTAGEN 20 23 Missing: Abolishes binding to heparin,
FT lipid A, lysozyme and DNA.
FT MUTAGEN 20 22 Missing: Greatly impairs binding to
FT heparin, lipid A, lysozyme and DNA.
FT Impairs antibacterial activity.
FT MUTAGEN 20 21 Missing: Impairs binding to heparin,
FT lipid A, lysozyme and DNA.
FT MUTAGEN 79 79 D->S: Impairs iron binding and changes
FT domain closure.
FT MUTAGEN 92 92 K->A: Almost no protease activity.
FT MUTAGEN 140 140 R->D,E,S: Disrupts anion binding site and
FT destabilizes iron binding.
FT MUTAGEN 229 229 R->G,E: Destabilizes iron binding
FT slightly.
FT MUTAGEN 229 229 R->K,L: Destabilizes iron binding
FT significantly.
FT MUTAGEN 270 270 P->V: No effect.
FT MUTAGEN 272 272 H->A,C,G,E,F,L,M,P,Q,T,Y: Destabilizes
FT iron binding.
FT MUTAGEN 278 278 S->A: No protease activity.
FT CONFLICT 14 14 L -> P (in Ref. 17; AAA58656).
FT CONFLICT 21 21 R -> S (in Ref. 14; AAH15822/AAH15823).
FT CONFLICT 36 36 T -> D (in Ref. 22; AA sequence).
FT CONFLICT 49 49 R -> C (in Ref. 14; AAH22347).
FT CONFLICT 130 130 G -> C (in Ref. 14; AAH15823).
FT CONFLICT 138 138 L -> R (in Ref. 14; AAH22347).
FT CONFLICT 140 140 Missing (in Ref. 18; AA sequence).
FT CONFLICT 169 169 Missing (in Ref. 18; AA sequence).
FT CONFLICT 409 410 DA -> NASVLMDSEGGFLAR (in Ref. 18; AA
FT sequence).
FT CONFLICT 415 415 G -> E (in Ref. 17; AAA59511).
FT CONFLICT 431 431 A -> G (in Ref. 17; AAA58656).
FT CONFLICT 456 456 A -> T (in Ref. 14; AAH15822/AAH15823).
FT CONFLICT 487 487 G -> A (in Ref. 25; AAA86665).
FT CONFLICT 531 531 Q -> E (in Ref. 18; AA sequence).
FT CONFLICT 537 537 V -> E (in Ref. 14; AAH15822).
FT CONFLICT 694 694 K -> R (in Ref. 18; AA sequence and 26;
FT AA sequence).
FT STRAND 24 31
FT HELIX 32 47
FT STRAND 50 52
FT STRAND 53 57
FT HELIX 61 69
FT STRAND 75 78
FT HELIX 80 87
FT TURN 89 91
FT STRAND 93 102
FT STRAND 104 118
FT STRAND 119 121
FT HELIX 125 127
FT STRAND 132 136
FT TURN 141 144
FT HELIX 145 151
FT HELIX 152 154
FT TURN 159 161
FT HELIX 164 171
FT STRAND 172 176
FT TURN 182 184
FT HELIX 186 188
FT TURN 189 191
FT HELIX 196 198
FT STRAND 206 208
FT HELIX 210 219
FT STRAND 224 229
FT HELIX 232 236
FT HELIX 240 243
FT STRAND 246 250
FT TURN 251 253
FT STRAND 254 257
FT HELIX 258 263
FT STRAND 266 270
FT STRAND 273 280
FT HELIX 283 297
FT TURN 299 301
FT STRAND 317 319
FT STRAND 325 328
FT HELIX 335 339
FT HELIX 341 348
FT HELIX 349 351
FT HELIX 354 362
FT STRAND 363 370
FT HELIX 371 383
FT TURN 384 386
FT STRAND 387 395
FT HELIX 396 404
FT STRAND 410 413
FT HELIX 415 423
FT STRAND 427 434
FT STRAND 436 439
FT STRAND 440 442
FT HELIX 446 448
FT STRAND 454 463
FT HELIX 469 471
FT STRAND 475 480
FT TURN 485 488
FT HELIX 489 499
FT HELIX 504 506
FT STRAND 508 512
FT STRAND 514 516
FT HELIX 521 523
FT TURN 533 536
FT HELIX 546 555
FT STRAND 560 565
FT HELIX 566 570
FT STRAND 573 576
FT HELIX 580 583
FT HELIX 587 589
FT STRAND 590 593
FT STRAND 599 601
FT HELIX 602 607
FT STRAND 610 613
FT STRAND 617 620
FT HELIX 622 624
FT HELIX 625 639
FT STRAND 640 642
FT TURN 646 649
FT STRAND 655 657
FT STRAND 666 670
FT HELIX 678 682
FT HELIX 684 696
FT HELIX 700 709
SQ SEQUENCE 710 AA; 78182 MW; 0489CABA6D13C098 CRC64;
MKLVFLVLLF LGALGLCLAG RRRSVQWCAV SQPEATKCFQ WQRNMRKVRG PPVSCIKRDS
PIQCIQAIAE NRADAVTLDG GFIYEAGLAP YKLRPVAAEV YGTERQPRTH YYAVAVVKKG
GSFQLNELQG LKSCHTGLRR TAGWNVPIGT LRPFLNWTGP PEPIEAAVAR FFSASCVPGA
DKGQFPNLCR LCAGTGENKC AFSSQEPYFS YSGAFKCLRD GAGDVAFIRE STVFEDLSDE
AERDEYELLC PDNTRKPVDK FKDCHLARVP SHAVVARSVN GKEDAIWNLL RQAQEKFGKD
KSPKFQLFGS PSGQKDLLFK DSAIGFSRVP PRIDSGLYLG SGYFTAIQNL RKSEEEVAAR
RARVVWCAVG EQELRKCNQW SGLSEGSVTC SSASTTEDCI ALVLKGEADA MSLDGGYVYT
AGKCGLVPVL AENYKSQQSS DPDPNCVDRP VEGYLAVAVV RRSDTSLTWN SVKGKKSCHT
AVDRTAGWNI PMGLLFNQTG SCKFDEYFSQ SCAPGSDPRS NLCALCIGDE QGENKCVPNS
NERYYGYTGA FRCLAENAGD VAFVKDVTVL QNTDGNNNEA WAKDLKLADF ALLCLDGKRK
PVTEARSCHL AMAPNHAVVS RMDKVERLKQ VLLHQQAKFG RNGSDCPDKF CLFQSETKNL
LFNDNTECLA RLHGKTTYEK YLGPQYVAGI TNLKKCSTSP LLEACEFLRK
//

MIM 150210
*RECORD*
*FIELD* NO
150210
*FIELD* TI
*150210 LACTOTRANSFERRIN; LTF
;;LACTOFERRIN; LF
*FIELD* TX

DESCRIPTION

Lactoferrin is an iron-binding glycoprotein of the transferrin (TF;
read more190000) family that is expressed in most biologic fluids and is a major
component of mammals' innate immune system (Legrand et al., 2008).

CLONING

Yang et al. (1983) cloned human cDNA for lactotransferrin.

Powell and Ogden (1990) reported the nucleotide sequence of human
lactoferrin cDNA. The deduced protein contains 709 amino acids,
including a 17-amino acid putative signal peptide.

In a review, Legrand et al. (2008) stated that the mature LF protein
contains 690 amino acids and is highly basic. It has a positively
charged N terminus that shares 40% sequence identity with the C
terminus. LF shares 60% amino acid identity with TF.

GENE FUNCTION

Gallin (1990) doubted that the structural gene for lactoferrin is the
site of mutation causing neutrophil lactoferrin deficiency (245480)
because the disorder appears to involve abnormal packaging of all
neutrophil-specific granule contents.

Bezault et al. (1994) found that Lf inhibited solid tumor growth and
tumor metastasis in mice. Natural killer cells appeared to be involved
in Lf antimetastatic activity in mouse tumor models.

Haemophilus influenzae is a major cause of otitis media and other
respiratory tract disease in children. The pathogenesis of the disease
begins with colonization of the upper respiratory mucosa, a process that
involves evasion of local immune mechanisms and adherence to epithelial
cells. Several studies demonstrated that human milk is protective
against H. influenzae colonization and disease. Qiu et al. (1998)
examined the effect of human milk on 2 autotransported proteins of H.
influenzae that are presumed to facilitate colonization: IgA1 protease
and Hap adhesin. They found that human milk lactoferrin efficiently
extracted the IgA1 protease preprotein from the bacterial outer
membrane. In addition, lactoferrin specifically degraded the Hap adhesin
and abolished Hap-mediated adherence. The results suggested that human
milk lactoferrin attenuates the pathogenic potential of H. influenzae by
selectively inactivating IgA1 protease and Hap, thereby interfering with
colonization. They suggested that future studies should examine the
therapeutic potential of lactoferrin, perhaps as a supplement in infant
formulas.

Human T-cell leukemia virus-1 (HTLV-1) causes T-cell leukemia and
lymphoma and is clustered in certain geographic areas. Like HIV-1
infection, HTLV-1 infection can be transmitted vertically through breast
milk. Refraining from breast feeding was found to efficiently block
mother-to-infant transmission in southwestern Japan. Moriuchi and
Moriuchi (2001) observed a dose-dependent enhancement of HTLV-1
replication by transactivating the viral long terminal repeat in cells
stimulated with human or bovine lactoferrin. Lactoferrin also
accelerated transmission to uninfected cord blood mononuclear cells.
Moriuchi and Moriuchi (2001) confirmed that lactoferrin inhibits HIV-1
replication and showed that it does so by nonspecifically blocking viral
fusion to cells.

Singh et al. (2002) hypothesized that the innate immune system possesses
specific activity to protect against biofilm infections and demonstrated
that lactoferrin, a ubiquitous and abundant constituent of human
external secretions, blocks biofilm development by the opportunistic
pathogen Pseudomonas aeruginosa. This occurs at lactoferrin
concentrations below those that kill or prevent growth. By chelating
iron, lactoferrin stimulates twitching, a specialized form of surface
motility, causing the bacteria to wander across the surface instead of
forming cell clusters and biofilms. Singh et al. (2002) concluded that
their findings reveal a specific antibiofilm defense mechanism acting at
a critical juncture in biofilm development.

In a review of LF structure and function, Legrand et al. (2008) stated
that LF downregulates proinflammatory cytokine and reactive oxygen
species production. A number of pathogens have lactoferrin-binding
molecules, and LF has antimicrobial activity, partly due to its metal
and ion chelation properties.

Using clarified saliva and biotinylated human herpesvirus-8 (HHV-8),
which is also known as Kaposi sarcoma (148000)-associated herpesvirus
(KSHV), Grange et al. (2005) detected binding to the 78-kD LF protein.
Binding did not require glycosylation. Approximately 8% of
HHV-8-uninfected individuals tested expressed a form of LF that was not
recognized by HHV-8. Endoprotease cleavage of native LF generated a
nonglycosylated 8-kD peptide corresponding to amino acids 606 to 679 in
the C-terminal region of LF that bound HHV-8. Grange et al. (2005)
concluded that LF in saliva is a ligand for HHV-8 and possibly a carrier
of viral particles.

Grange et al. (2012) showed that LF or the 8-kD LF C-terminal peptide
enhanced KSHV infection of a human epithelial cell line and primary
human foreskin fibroblasts.

GENE STRUCTURE

Kim et al. (1998) determined that the LF gene contains 17 exons and
spans 24.5 kb.

MAPPING

Mouse cDNA for lactotransferrin was used by Naylor et al. (1987) to map
the gene in mouse and in man. Southern blot analysis of somatic cell
hybrid DNA and in situ hybridization placed the LTF gene in the 3q21-q23
region, where transferrin is also located (McCombs et al., 1988). Naylor
et al. (1987) and Teng et al. (1987) found, furthermore, that in the
mouse LTF sequences are located on chromosome 9, where the transferrin
gene is also located in that species. Because of the high degree of
homology between transferrin and lactoferrin (about 80% at the amino
acid level), it is possible that these 2 genes are very close to each
other.

By FISH, Kim et al. (1998) mapped the LF gene to chromosome 3p21.3.

ANIMAL MODEL

Ward et al. (2003) developed lactoferrin-null mice and found them to be
viable and fertile. They developed normally and displayed no overt
abnormalities. Lactoferrin was not required for intestinal iron uptake,
and relatively normal iron parameters were observed in lactoferrin-null
mice. In situ hybridization of wildtype animals demonstrated that
lactoferrin is not expressed in the postnatal or adult intestine. Ward
et al. (2003) concluded that the functional role of this protein in the
intestine during the postnatal period is likely imparted by maternal
milk-derived lactoferrin.

MOLECULAR GENETICS

Velliyagounder et al. (2003) characterized a lys/arg polymorphism at
position 29 in human LF that results from a SNP in exon 1. LF variants
containing lys29 or arg29 exhibited nearly identical iron-binding and
iron-releasing activities and equivalent bactericidal activities against
a strain of the gram-negative bacterium Actinobacillus
actinomycetemcomitans. However, LF containing lys29 exhibited
significantly greater bactericidal activity against the gram-negative
species Streptococcus mutans and Streptococcus mitis than did LF
containing arg29. In addition, LF with lys29 stimulated bovine tracheal
epithelial cells to synthesize much higher levels of tracheal
antimicrobial peptide (TAP; 602560) than did LF with arg29. Lys29 and
arg29 had allele frequencies of 24% and 76%, respectively, among 17
healthy humans, and 72% and 28%, respectively, among 9 patients with
localized juvenile periodontitis.

*FIELD* SA
Rado et al. (1987)
*FIELD* RF
1. Bezault, J.; Bhimani, R.; Wiprovnick, J.; Furmanski, P.: Human
lactoferrin inhibits growth of solid tumors and development of experimental
metastases in mice. Cancer Res. 54: 2310-2312, 1994.

2. Gallin, J. I.: Personal Communication. Bethesda, Md. 10/12/1990.

3. Grange, P. A.; Gressier, L.; Williams, J. F.; Dyson, O. F.; Akula,
S. M.; Dupin, N.: Cloning a human saliva-derived peptide for preventing
KSHV transmission. (Letter) J. Invest. Derm. 132: 1733-1735, 2012.

4. Grange, P. A.; Marcelin, A.-G.; Calvez, V.; Chauvel, C.; Escande,
J.-P.; Dupin, N.: Salivary lactoferrin is recognized by the human
herpesvirus-8. J. Invest. Derm. 124: 1249-1258, 2005.

5. Kim, S. J.; Yu, D.-Y.; Pak, K.-W.; Jeong, S.; Kim, S.-W.; Lee,
K.-K.: Structure of the human lactoferrin gene and its chromosomal
localization. Molec. Cells 8: 663-668, 1998.

6. Legrand, D.; Pierce, A.; Elass, E.; Carpentier, M.; Mariller, C.;
Mazurier, J.: Lactoferrin structure and functions. Adv. Exp. Med.
Biol. 606: 163-194, 2008.

7. Legrand, D.; Pierce, A.; Elass, E.; Carpentier, M.; Mariller, C.;
Mazurier, J.: Lactoferrin structure and functions. Adv. Exp. Med.
Biol. 606: 163, and 194, 2008.

8. McCombs, J. L.; Teng, C. T.; Pentecost, B. T.; Magnuson, V. L.;
Moore, C. M.; McGill, J. R.: Chromosomal localization of human lactotransferrin
gene (LTF) by in situ hybridization. Cytogenet. Cell Genet. 47:
16-17, 1988.

9. Moriuchi, M.; Moriuchi, H.: A milk protein lactoferrin enhances
human T cell leukemia virus type I and suppresses HIV-1 infection. J.
Immun. 166: 4231-4236, 2001.

10. Naylor, S. L.; Marshall, A.; Solomon, A.; McGill, J. R.; McCombs,
J.; Magnuson, V. L.; Moore, C. M.; Lalley, P. A.; Pentecost, B. T.;
Teng, C.: Lactoferrin maps to human chromosome 3(q21-q23) and mouse
chromosome 9. (Abstract) Cytogenet. Cell Genet. 46: 669 only, 1987.

11. Powell, M. J.; Ogden, J. E.: Nucleotide sequence of human lactoferrin
cDNA. Nucleic Acids Res. 18: 4013 only, 1990.

12. Qiu, J.; Hendrixson, D. R.; Baker, E. N.; Murphy, T. F.; St. Geme,
J. W., III; Plaut, A. G.: Human milk lactoferrin inactivates two
putative colonization factors expressed by Haemophilus influenzae. Proc.
Nat. Acad. Sci. 95: 12641-12646, 1998.

13. Rado, T. A.; Wei, X.; Benz, E. J., Jr.: Isolation of lactoferrin
cDNA from a human myeloid library and expression of mRNA during normal
and leukemic myelopoiesis. Blood 70: 989-993, 1987.

14. Singh, P. K.; Parsek, M. R.; Greenberg, E. P.; Welsh, M. J.:
A component of innate immunity prevents bacterial biofilm development. Nature 417:
552-555, 2002.

15. Teng, C. T.; Pentecost, B. T.; Marshall, A.; Solomon, A.; Bowman,
B. H.; Lalley, P. A.; Naylor, S. L.: Assignment of the lactotransferrin
gene to human chromosome 3 and to mouse chromosome 9. Somat. Cell
Molec. Genet. 13: 689-693, 1987.

16. Velliyagounder, K.; Kaplan, J. B.; Furgang, D.; Legarda, D.; Diamond,
G.; Parkin, R. E.; Fine, D. H.: One of two human lactoferrin variants
exhibits increased antibacterial and transcriptional activation activities
and is associated with localized juvenile periodontitis. Infect.
Immun. 71: 6141-6147, 2003.

17. Ward, P. P.; Mendoza-Meneses, M.; Cunningham, G. A.; Conneely,
O. M.: Iron status in mice carrying a targeted disruption of lactoferrin. Molec.
Cell. Biol. 23: 178-185, 2003.

18. Yang, F.; Lum, J.; Baldwin, W. D.; Brune, J. L.; van Bragt, P.;
Bowman, B. H.: Genetic analysis of human iron binding glycoproteins.
(Abstract) Am. J. Hum. Genet. 35: 184A only, 1983.

*FIELD* CN
Paul J. Converse - updated: 6/4/2012
Matthew B. Gross - updated: 7/9/2008
Paul J. Converse - updated: 5/27/2008
Patricia A. Hartz - updated: 2/27/2003
Ada Hamosh - updated: 5/28/2002
Paul J. Converse - updated: 4/30/2001
Victor A. McKusick - updated: 11/2/1998

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
mgross: 06/12/2012
terry: 6/4/2012
carol: 11/5/2009
mgross: 7/9/2008
terry: 5/27/2008
mgross: 4/25/2008
joanna: 4/25/2008
terry: 3/16/2005
mgross: 2/27/2003
alopez: 5/29/2002
terry: 5/28/2002
mgross: 4/30/2001
carol: 11/9/1998
terry: 11/2/1998
supermim: 3/16/1992
carol: 3/3/1992
carol: 11/8/1990
carol: 9/26/1990
supermim: 3/20/1990
ddp: 10/27/1989

MIM 245480
*RECORD*
*FIELD* NO
245480
*FIELD* TI
#245480 SPECIFIC GRANULE DEFICIENCY; SGD
;;LACTOFERRIN-DEFICIENT NEUTROPHILS;;
NEUTROPHIL LACTOFERRIN DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because the disorder can be
caused by mutation in the CEBPE gene (600749), which encodes a
myeloid-specific transcription factor.

In mammals, neutrophils contain 2 principal types of granules. The first
type, azurophil granules, appear early in neutrophil development and
contain lysosomal enzymes, lysozyme, and myeloperoxidase (MPO). The
second type, specific granules, are formed later, lack MPO and
hydrolases, but contain lactoferrin and the remainder of the cell's
complement of lysozyme. Campbell (1982) presented evidence that
lactoferrin shares binding to a specific receptor of alveolar
macrophages with 2 other neutrophil granule glycoproteins, cathepsin G
and leukocyte elastase. Lactoferrin (also known as lactotransferrin) is
a member of the family of iron-binding proteins. Lactoferrin is widely
distributed in exocrine secretions, notably milk, and is an important
component of leukocytes. It has strong bacteriostatic properties. These
result from its avidity for iron, depriving bacteria of iron essential
for growth. It may also protect cells from free radical damage by
binding potentially catalytic free iron. Anderson et al. (1987) studied
the structure of human lactoferrin, which bears many resemblances to
transferrin (190000).

Johnston (1982) stated that approximately 15 primary (presumably
congenital) defects of neutrophil function associated with recurrent
infections had been described to that date, and at least 30 additional
conditions had been reported in which decreased neutrophil function had
been reasonably well documented to be a consequence of another, primary
disease. Specific granules are detected at the electron microscopic
level by cytochemical demonstration of their lack of MPO and at the
light microscopic level by positive immunochemical staining for
lactoferrin with the use of specific antisera. Breton-Gorius et al.
(1980) found total lack of specific granules (and lactoferrin) in a
6-year-old boy with recurrent infections. Neutrophils also exhibited
abnormal nuclear segmentation, nuclear clefts, abnormally weak
cytochemical reaction for alkaline phosphatase, and an increased number
of mitochondria and ribosomes. Degranulation of azurophil granules
occurred normally following phagocytosis. Neutrophil count was normal.
The parents were first cousins; a sister had died at the age of 1 year
of an infection. Reports of possibly identical cases were found. Whether
the defect lies in the synthesis of lactoferrin itself or represents
failure of specific granule production is not clear. Boxer et al. (1982)
restudied a patient reported by Strauss et al. (1974).

Ganz et al. (1988) found that both patients with SGD whom they studied
had almost complete absence of defensins, which in normal cells
constitute more than 30% of the protein of azurophil granules. The
polymorphonuclear leukocytes from these patients contained normal or
mildly decreased amounts of cathepsin and elastase, these being
components of polymorphonuclear leukocytes with microbicidal/cytotoxic
activity that are found to be absent in patients with Chediak-Higashi
syndrome (214500). Lomax et al. (1989) studied mRNA transcription and
protein synthesis of 2 neutrophil granule proteins, lactoferrin and
myeloperoxidase, in SGD. Whereas nucleated marrow cells produced normal
amounts of myeloperoxidase, there was no detectable synthesis of
lactoferrin. Transcripts of the expected size for lactoferrin were
detectable in the nucleated marrow cells of 2 SGD patients, but were
markedly diminished in abundance when compared with the RNA of normal
cells. Because lactoferrin is secreted by the glandular epithelia of
several tissues, Lomax et al. (1989) also assessed lactoferrin in the
nasal secretions of 1 SGD patient. Nasal secretory lactoferrin was of
the same molecular weight as neutrophil lactoferrin and was secreted in
normal amounts. From these data, Lomax et al. (1989) concluded that
lactoferrin deficiency in SGD neutrophils is tissue specific and is
secondary to an abnormality of RNA production. Gallin (1990) suggested
that since there is abnormal packaging of all neutrophil specific
granule contents in neutrophil lactoferrin deficiency, a defective
granule packaging gene may be involved.

Gombart et al. (2001) stated that only 5 cases of SGD had been reported
worldwide. Neutrophils of individuals with SGD display atypical bilobed
nuclei, lack expression of all secondary and tertiary granule proteins,
and possess defects in chemotaxis, disaggregation, receptor
upregulation, and bactericidal activity, resulting in frequent and
severe bacterial infections. Since SGD individuals express normal levels
of lactoferrin and transcobalamin in their saliva but not in either
their plasma or neutrophils, the molecular basis for SGD was
hypothesized to involve a mutation in a myeloid-specific transcription
factor. The CEBPE gene (600749) encodes such a transcription factor,
which is expressed primarily during granulocytic differentiation.
Targeted disruption of the Cebpe gene in mice leads to defects in
terminal differentiation of neutrophils with phenotypic and functional
defects closely paralleling those of SGD. Mutations in the CEBPE gene
were demonstrated by Lekstrom-Himes et al. (1999) and Gombart et al.
(2001); see 600749.0001 and 600749.0002. In each case the mutation was
present in homozygous form and both parents were heterozygous. The
patient of Lekstrom-Himes et al. (1999) was the offspring of first
cousins once removed.

*FIELD* RF
1. Anderson, B. F.; Baker, H. M.; Dodson, E. J.; Norris, G. E.; Rumball,
S. V.; Waters, J. M.; Baker, E. N.: Structure of human lactoferrin
at 3.2-angstrom resolution. Proc. Nat. Acad. Sci. 84: 1769-1773,
1987.

2. Boxer, L. A.; Coates, T. D.; Haak, R. A.; Wolach, J. B.; Hoffstein,
S.; Baehner, R. L.: Lactoferrin deficiency associated with altered
granulocyte function. New Eng. J. Med. 307: 404-410, 1982.

3. Breton-Gorius, J.; Mason, D. Y.; Buriot, D.; Vilde, J.-L.; Griscelli,
C.: Lactoferrin deficiency as a consequence of a lack of specific
granules in neutrophils from a patient with recurrent infections:
detection by immunoperoxidase staining for lactoferrin and cytochemical
electron microscopy. Am. J. Path. 99: 413-428, 1980.

4. Campbell, E. J.: Human leukocyte elastase, cathepsin G, and lactoferrin:
family of neutrophil granule glycoproteins that bind to an alveolar
macrophage receptor. Proc. Nat. Acad. Sci. 79: 6941-6945, 1982.

5. Gallin, J. I.: Personal Communication. Bethesda, Md. 10/12/1990.

6. Ganz, T.; Metcalf, J. A.; Gallin, J. I.; Boxer, L. A.; Lehrer,
R. I.: Microbicidal/cytotoxic proteins of neutrophils are deficient
in two disorders: Chediak-Higashi syndrome and 'specific' granule
deficiency. J. Clin. Invest. 82: 552-556, 1988.

7. Gombart, A. F.; Shiohara, M.; Kwok, S. H.; Agematsu, K.; Komiyama,
A.; Koeffler, H. P.: Neutrophil-specific granule deficiency: homozygous
recessive inheritance of a frameshift mutation in the gene encoding
transcription factor CCAAT/enhancer binding protein-epsilon. Blood 97:
2561-2567, 2001.

8. Johnston, R. B., Jr.: Defects in neutrophil function. (Editorial) New
Eng. J. Med. 307: 434-436, 1982.

9. Lekstrom-Himes, J. A.; Dorman, S. E.; Kopar, P.; Holland, S. M.;
Gallin, J. I.: Neutrophil-specific granule deficiency results from
a novel mutation with loss of function of the transcription factor
CCAAT/enhancer binding protein-epsilon. J. Exp. Med. 189: 1847-1852,
1999.

10. Lomax, K. J.; Gallin, J. I.; Rotrosen, D.; Raphael, G. D.; Kaliner,
M. A.; Benz, E. J., Jr.; Boxer, L. A.; Malech, H. L.: Selective defect
in myeloid cell lactoferrin gene expression in neutrophil specific
granule deficiency. J. Clin. Invest. 83: 514-519, 1989.

11. Strauss, R. G.; Bove, K. E.; Jones, J. F.; Mauer, A. M.; Fulginiti,
V. A.: An anomaly of neutrophil morphology with impaired function. New
Eng. J. Med. 290: 478-484, 1974.

*FIELD* CS

Misc:
Recurrent infections

Lab:
Absent neutrophil specific granules;
Absent neutrophil lactoferrin;
Abnormal neutrophil nuclear segmentation;
Neutrophil nuclear clefts;
Low neutrophil alkaline phosphatase;
Increased neutrophil mitochondria and ribosomes;
Normal degranulation of azurophil granules after phagocytosis;
Normal neutrophil count

Inheritance:
Autosomal recessive

*FIELD* CN
Victor A. McKusick - updated: 7/17/2001

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
mcapotos: 12/27/2001
mcapotos: 8/10/2001
mcapotos: 8/7/2001
mcapotos: 7/18/2001
terry: 7/17/2001
terry: 5/7/1994
mimadm: 2/19/1994
supermim: 3/16/1992
carol: 11/8/1990
carol: 9/26/1990
supermim: 3/20/1990