RBCC

Full text data of CYCS

CYCS (CYC) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Cytochrome c

UniProt P99999
ID CYC_HUMAN Reviewed; 105 AA.
AC P99999; A4D166; B2R4I1; P00001; Q6NUR2; Q6NX69; Q96BV4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 120.
DE RecName: Full=Cytochrome c;
GN Name=CYCS; Synonyms=CYC;
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 [GENOMIC DNA].
RX PubMed=2849112; DOI=10.1073/pnas.85.24.9625;
RA Evans M.J., Scarpulla R.C.;
RT "The human somatic cytochrome c gene: two classes of processed
RT pseudogenes demarcate a period of rapid molecular evolution.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:9625-9629(1988).
RN [2]
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 (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Amygdala;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [7]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Bone marrow, Brain, Kidney, Lung, Skeletal muscle, Skin,
RC Testis, and Urinary bladder;
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 [9]
RP PROTEIN SEQUENCE OF 2-105, AND ACETYLATION AT GLY-2.
RC TISSUE=Heart;
RX PubMed=13933734;
RA Matsubara H., Smith E.L.;
RT "The amino acid sequence of human heart cytochrome c.";
RL J. Biol. Chem. 237:3575-3576(1962).
RN [10]
RP PROTEIN SEQUENCE OF 2-105.
RC TISSUE=Heart;
RX PubMed=14063298;
RA Matsubara H., Smith E.L.;
RT "Human heart cytochrome c. Chymotryptic peptides, tryptic peptides,
RT and the complete amino acid sequence.";
RL J. Biol. Chem. 238:2732-2753(1963).
RN [11]
RP REVIEW ON ROLE IN APOPTOSIS.
RX PubMed=9515723; DOI=10.1016/S0014-5793(98)00061-1;
RA Skulachev V.P.;
RT "Cytochrome c in the apoptotic and antioxidant cascades.";
RL FEBS Lett. 423:275-280(1998).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [13]
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 [14]
RP STRUCTURE BY NMR.
RA Jeng W.-Y., Shiu J.-H., Tsai Y.-H., Chuang W.-J.;
RT "Solution structure of reduced recombinant human cytochrome c.";
RL Submitted (FEB-2003) to the PDB data bank.
RN [15]
RP VARIANT THC4 SER-42, MASS SPECTROMETRY, CHARACTERIZATION OF VARIANT
RP THC4 SER-42, AND X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF VARIANT
RP THC4 SER-42 AND WILD TYPE.
RX PubMed=18345000; DOI=10.1038/ng.103;
RA Morison I.M., Cramer Borde E.M.C., Cheesman E.J., Cheong P.L.,
RA Holyoake A.J., Fichelson S., Weeks R.J., Lo A., Davies S.M.K.,
RA Wilbanks S.M., Fagerlund R.D., Ludgate M.W., da Silva Tatley F.M.,
RA Coker M.S.A., Bockett N.A., Hughes G., Pippig D.A., Smith M.P.,
RA Capron C., Ledgerwood E.C.;
RT "A mutation of human cytochrome c enhances the intrinsic apoptotic
RT pathway but causes only thrombocytopenia.";
RL Nat. Genet. 40:387-389(2008).
CC -!- FUNCTION: Electron carrier protein. The oxidized form of the
CC cytochrome c heme group can accept an electron from the heme group
CC of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c
CC then transfers this electron to the cytochrome oxidase complex,
CC the final protein carrier in the mitochondrial electron-transport
CC chain.
CC -!- FUNCTION: Plays a role in apoptosis. Suppression of the anti-
CC apoptotic members or activation of the pro-apoptotic members of
CC the Bcl-2 family leads to altered mitochondrial membrane
CC permeability resulting in release of cytochrome c into the
CC cytosol. Binding of cytochrome c to Apaf-1 triggers the activation
CC of caspase-9, which then accelerates apoptosis by activating other
CC caspases.
CC -!- INTERACTION:
CC O14727:APAF1; NbExp=6; IntAct=EBI-446479, EBI-446492;
CC -!- SUBCELLULAR LOCATION: Mitochondrion intermembrane space.
CC Note=Loosely associated with the inner membrane.
CC -!- PTM: Binds 1 heme group per subunit.
CC -!- PTM: Phosphorylation at Tyr-49 and Tyr-98 both reduce by half the
CC turnover in the reaction with cytochrome c oxidase, down-
CC regulating mitochondrial respiration (By similarity).
CC -!- DISEASE: Thrombocytopenia 4 (THC4) [MIM:612004]: Thrombocytopenia
CC is defined by a decrease in the number of platelets in circulating
CC blood, resulting in the potential for increased bleeding and
CC decreased ability for clotting. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cytochrome c family.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Life shuttle - Issue 76
CC of November 2006;
CC URL="http://web.expasy.org/spotlight/back_issues/sptlt076.shtml";
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DR EMBL; M22877; AAA35732.1; -; Genomic_DNA.
DR EMBL; BT006946; AAP35592.1; -; mRNA.
DR EMBL; AK311836; BAG34778.1; -; mRNA.
DR EMBL; AL713681; CAD28485.1; -; mRNA.
DR EMBL; AC007487; AAQ96844.1; -; Genomic_DNA.
DR EMBL; CH236948; EAL24239.1; -; Genomic_DNA.
DR EMBL; CH471073; EAW93822.1; -; Genomic_DNA.
DR EMBL; BC005299; AAH05299.1; -; mRNA.
DR EMBL; BC008475; AAH08475.1; -; mRNA.
DR EMBL; BC008477; AAH08477.1; -; mRNA.
DR EMBL; BC009578; AAH09578.1; -; mRNA.
DR EMBL; BC009579; AAH09579.1; -; mRNA.
DR EMBL; BC009582; AAH09582.1; -; mRNA.
DR EMBL; BC009587; AAH09587.1; -; mRNA.
DR EMBL; BC009602; AAH09602.1; -; mRNA.
DR EMBL; BC009607; AAH09607.1; -; mRNA.
DR EMBL; BC014359; AAH14359.1; -; mRNA.
DR EMBL; BC014361; AAH14361.1; -; mRNA.
DR EMBL; BC015130; AAH15130.1; -; mRNA.
DR EMBL; BC016006; AAH16006.1; -; mRNA.
DR EMBL; BC021994; AAH21994.1; -; mRNA.
DR EMBL; BC022330; AAH22330.1; -; mRNA.
DR EMBL; BC067222; AAH67222.1; -; mRNA.
DR EMBL; BC068464; AAH68464.1; -; mRNA.
DR EMBL; BC070156; AAH70156.1; -; mRNA.
DR EMBL; BC070346; AAH70346.1; -; mRNA.
DR EMBL; BC071761; AAH71761.1; -; mRNA.
DR PIR; A31764; CCHU.
DR RefSeq; NP_061820.1; NM_018947.5.
DR UniGene; Hs.437060; -.
DR UniGene; Hs.617193; -.
DR PDB; 1J3S; NMR; -; A=2-104.
DR PDB; 3NWV; X-ray; 1.90 A; A/B/C/D=2-105.
DR PDB; 3ZCF; X-ray; 1.65 A; A/B/C/D=2-105.
DR PDB; 3ZOO; X-ray; 1.35 A; A/B/C/D=2-105.
DR PDBsum; 1J3S; -.
DR PDBsum; 3NWV; -.
DR PDBsum; 3ZCF; -.
DR PDBsum; 3ZOO; -.
DR ProteinModelPortal; P99999; -.
DR SMR; P99999; 2-105.
DR DIP; DIP-29683N; -.
DR IntAct; P99999; 7.
DR MINT; MINT-3023956; -.
DR STRING; 9606.ENSP00000307786; -.
DR DrugBank; DB01065; Melatonin.
DR DrugBank; DB01017; Minocycline.
DR PhosphoSite; P99999; -.
DR DMDM; 42560196; -.
DR PaxDb; P99999; -.
DR PeptideAtlas; P99999; -.
DR PRIDE; P99999; -.
DR DNASU; 54205; -.
DR Ensembl; ENST00000305786; ENSP00000307786; ENSG00000172115.
DR Ensembl; ENST00000409409; ENSP00000386270; ENSG00000172115.
DR Ensembl; ENST00000409764; ENSP00000387279; ENSG00000172115.
DR GeneID; 54205; -.
DR KEGG; hsa:54205; -.
DR UCSC; uc003sxl.3; human.
DR CTD; 54205; -.
DR GeneCards; GC07M025158; -.
DR HGNC; HGNC:19986; CYCS.
DR HPA; CAB004222; -.
DR HPA; CAB005126; -.
DR HPA; CAB018597; -.
DR MIM; 123970; gene.
DR MIM; 612004; phenotype.
DR neXtProt; NX_P99999; -.
DR Orphanet; 168629; Autosomal thrombocytopenia with normal platelets.
DR PharmGKB; PA134981636; -.
DR eggNOG; COG3474; -.
DR HOGENOM; HOG000009762; -.
DR HOVERGEN; HBG003023; -.
DR InParanoid; P99999; -.
DR KO; K08738; -.
DR OMA; WNEETLM; -.
DR OrthoDB; EOG761BWX; -.
DR PhylomeDB; P99999; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; CYCS; human.
DR EvolutionaryTrace; P99999; -.
DR GeneWiki; Cytochrome_c; -.
DR GenomeRNAi; 54205; -.
DR NextBio; 56526; -.
DR PRO; PR:P99999; -.
DR ArrayExpress; P99999; -.
DR Bgee; P99999; -.
DR CleanEx; HS_CYCS; -.
DR Genevestigator; P99999; -.
DR GO; GO:0005829; C:cytosol; IMP:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0005758; C:mitochondrial intermembrane space; TAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:LIFEdb.
DR GO; GO:0000159; C:protein phosphatase type 2A complex; TAS:UniProtKB.
DR GO; GO:0070469; C:respiratory chain; IEA:UniProtKB-KW.
DR GO; GO:0045155; F:electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; TAS:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0008635; P:activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c; TAS:UniProtKB.
DR GO; GO:0006309; P:apoptotic DNA fragmentation; IMP:UniProtKB.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0022904; P:respiratory electron transport chain; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR InterPro; IPR009056; Cyt_c-like_dom.
DR InterPro; IPR002327; Cyt_c_1A/1B.
DR InterPro; IPR003088; Cyt_c_dom.
DR PANTHER; PTHR11961; PTHR11961; 1.
DR Pfam; PF00034; Cytochrom_C; 1.
DR PRINTS; PR00604; CYTCHRMECIAB.
DR SUPFAM; SSF46626; SSF46626; 1.
DR PROSITE; PS51007; CYTC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Apoptosis; Complete proteome;
KW Direct protein sequencing; Disease mutation; Electron transport; Heme;
KW Iron; Metal-binding; Mitochondrion; Phosphoprotein; Polymorphism;
KW Reference proteome; Respiratory chain; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 105 Cytochrome c.
FT /FTId=PRO_0000108218.
FT METAL 19 19 Iron (heme axial ligand).
FT METAL 81 81 Iron (heme axial ligand).
FT BINDING 15 15 Heme (covalent).
FT BINDING 18 18 Heme (covalent).
FT MOD_RES 2 2 N-acetylglycine.
FT MOD_RES 49 49 Phosphotyrosine (By similarity).
FT MOD_RES 98 98 Phosphotyrosine (By similarity).
FT VARIANT 42 42 G -> S (in THC4; increases the pro-
FT apoptotic function by triggering caspase
FT activation more efficiently than wild-
FT type; does not affect the redox
FT function).
FT /FTId=VAR_044450.
FT VARIANT 56 56 K -> R (in dbSNP:rs11548795).
FT /FTId=VAR_048850.
FT VARIANT 66 66 M -> L (in 10% of the molecules).
FT /FTId=VAR_002204.
FT CONFLICT 18 18 C -> Y (in Ref. 8; AAH15130).
FT CONFLICT 41 41 T -> I (in Ref. 8; AAH68464).
FT HELIX 4 14
FT TURN 15 18
FT STRAND 23 25
FT STRAND 28 30
FT TURN 36 38
FT HELIX 51 55
FT HELIX 62 70
FT HELIX 72 75
FT HELIX 89 102
SQ SEQUENCE 105 AA; 11749 MW; 8EE9689E0102506B CRC64;
MGDVEKGKKI FIMKCSQCHT VEKGGKHKTG PNLHGLFGRK TGQAPGYSYT AANKNKGIIW
GEDTLMEYLE NPKKYIPGTK MIFVGIKKKE ERADLIAYLK KATNE
//

MIM 123970
*RECORD*
*FIELD* NO
123970
*FIELD* TI
*123970 CYTOCHROME C, SOMATIC; CYCS
;;CYTOCHROME C; CYC
*FIELD* TX

DESCRIPTION

Cytochrome c is located in the mitochondria of all aerobic cells and is
read moreinvolved in the electron transport system that functions in oxidative
phosphorylation. It accepts electrons from cytochrome b and transfers
them to cytochrome oxidase. In the process, the iron of the heme group,
which is identical to that of hemoglobin and myoglobin, shifts from the
ferrous to the ferric state (summary by Dayhoff, 1972).

CLONING

Human cytochrome c has 104 amino acid residues and a molecular mass of
11,458 Da (Dayhoff, 1972).

Evans and Scarpulla (1988) isolated and determined the nucleotide
sequences of the human somatic cytochrome c gene and 11 processed
pseudogenes. Zhang and Gerstein (2003) identified 49 processed CYCS
pseudogenes in the human genome, the oldest of which is orthologous to
the testis-specific cytochrome c gene in rodents. The human pseudogenes
are of 2 types: a predominant class of older pseudogenes originating
from a gene that most closely resembles the modern rodent gene, and a
second group of 4 young pseudogenes that originated from the more recent
primate gene.

GENE FUNCTION

In addition to its role in oxidative phosphorylation, release of
cytochrome c from the mitochondrial intermembrane space results in
nuclear apoptosis (Liu et al., 1996). Binding of APAF1 (602233) to
cytochrome c allows APAF1 to form a ternary complex with, and activate,
the initiator procaspase-9 (CASP9; 602234) in the presence of dATP (Li
et al., 1997). Active caspase-9 then turns on downstream effector
caspases, beginning the death cascade (summary by Earnshaw (1999)).

Boehning et al. (2003) presented evidence that mammalian cytochrome c
binds to inositol 1,4,5-trisphosphate receptors (see ITPR1; 147265)
during apoptosis. The addition of 1 nanomolar cytochrome c blocked
calcium-dependent inhibition of ITPR1 function in ITPR1-transfected COS
cells. Early in apoptosis, cytochrome c translocated to the endoplasmic
reticulum, where it selectively bound ITPR1, resulting in sustained
oscillatory cytosolic calcium increases. These calcium events were
linked to the coordinated release of cytochrome c from all mitochondria.

Chandra et al. (2006) showed that physiologic levels of nucleotides
inhibited cytochrome c-initiated apoptosome formation and caspase-9
activation by directly binding to several key lysines in cytochrome c
and thereby preventing interaction of cytochrome c with APAF1. In
various apoptotic systems, caspase activation was preceded by decreases
in overall intracellular nucleoside triphosphate (NTP) pools.
Microinjection of nucleotides inhibited, whereas reducing NTP pools
enhanced, both cytochrome c- and apoptotic stimuli-induced cell death.
Chandra et al. (2006) concluded that intracellular nucleotides represent
critical prosurvival factors.

MOLECULAR GENETICS

Morison et al. (2008) identified a 6-generation pedigree segregating
autosomal dominant transmission of thrombocytopenia (THC4; 612004). All
affected family members had a gly42-to-ser substitution (G42S;
123970.0001) in the CYSC gene. Glycine-42 is invariant among 113
eukaryotic species. Patients from this family had reduced platelet
production as the etiology of their thrombocytopenia. The mutation
increased the apoptotic activity of cytochrome c. Morison et al. (2008)
remarked that the observation that the members of the affected family
are otherwise healthy and long-lived implies that, at least in its
heterozygous form, the presence of a more 'active' cytochrome c has
little or no effect on the apoptotic outcome in most organs during
development and adult life.

ANIMAL MODEL

Li et al. (2000) generated murine embryonic stem cells with a targeted
disruption of the cytochrome c gene. Murine embryos devoid of cytochrome
c died in utero by midgestation, but cell lines established from early
cytochrome c null embryos were viable under conditions that compensated
for defective oxidative phosphorylation. As compared with cell lines
established from wildtype embryos, cells lacking cytochrome c showed
reduced caspase-3 (CASP3; 600636) activation and were resistant to the
proapoptotic effects of ultraviolet irradiation, serum withdrawal, and
staurosporine. In contrast, cells lacking cytochrome c demonstrated
increased sensitivity to cell death signals triggered by tumor necrosis
factor (TNF; 191160). These results established the role of cytochrome c
in different apoptotic signaling cascades.

*FIELD* AV
.0001
THROMBOCYTOPENIA, AUTOSOMAL DOMINANT, 4
CYCS, GLY42SER

In affected members of a 6-generation pedigree segregating autosomal
dominant nonsyndromic thrombocytopenia (THC4; 612004), Morison et al.
(2008) identified a 124G-A transition of the consensus coding sequence
of the CYCS gene, resulting in a gly42-to-ser (G42S) substitution.
Glycine-42 is invariant among 113 eukaryotic species. The mutation was
shown to increase the apoptotic activity of cytochrome c. Morison (2008)
pointed out that using the 104-amino acid sequence lacking the
initiating methionine (Dayhoff, 1972), the mutation affects codon 41
(GLY41SER).

*FIELD* RF
1. Boehning, D.; Patterson, R. L.; Sedaghat, L.; Glebova, N. O.; Kurosaki,
T.; Snyder, S. H.: Cytochrome c binds to inositol (1,4,5) trisphosphate
receptors, amplifying calcium-dependent apoptosis. Nature Cell Biol. 5:
1051-1061, 2003. Note: Erratum: Nature Cell Biol. 6 77 only, 2004.

2. Chandra, D.; Bratton, S. B.; Person, M. D.; Tian, Y.; Martin, A.
G.; Ayres, M.; Fearnhead, H. O.; Gandhi, V.; Tang, D. G.: Intracellular
nucleotides act as critical prosurvival factors by binding to cytochrome
c and inhibiting apoptosome. Cell 125: 1333-1346, 2006.

3. Dayhoff, M. O.: Atlas of Protein Sequence and Structure. Cytochrome
C group. Washington: National Biomedical Research Foundation (pub.)
5: 1972. Pp. D7-D27.

4. Earnshaw, W. C.: A cellular poison cupboard. Nature 397: 387-388,
1999.

5. Evans, M. J.; Scarpulla, R. C.: The human somatic cytochrome c
gene: two classes of processed pseudogenes demarcate a period of rapid
molecular evolution. Proc. Nat. Acad. Sci. 85: 9625-9629, 1988.

6. Li, K.; Li, Y.; Shelton, J. M.; Richardson, J. A.; Spencer, E.;
Chen, Z. J.; Wang, X.; Williams, R. S.: Cytochrome c deficiency causes
embryonic lethality and attenuates stress-induced apoptosis. Cell 101:
389-399, 2000.

7. Li, P.; Nijhawan, D.; Budihardjo, I.; Srinivasula, S. M.; Ahmad,
M.; Alnemri, E. S.; Wang, X.: Cytochrome c and dATP-dependent formation
of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:
479-489, 1997.

8. Liu, X.; Kim, C. N.; Yang, J.; Jemmerson, R.; Wang, X.: Induction
of apoptotic program in cell-free extracts: requirement for dATP and
cytochrome c. Cell 86: 147-157, 1996.

9. Morison, I. M.: Personal Communication. Dunedin, New Zealand
6/5/2008.

10. Morison, I. M.; Borde, E. M. C.; Cheesman, E. J.; Cheong, P. L.;
Holyoake, A. J.; Fichelson, S.; Weeks, R. J.; Lo, A.; Davies, S. M.
K.; Wilbanks, S. M.; Fagerlund, R. D.; Ludgate, M. W.; da Silva Tatley,
F. M.; Coker, M. S. A.; Bockett, N. A.; Hughes, G.; Pippig, D. A.;
Smith, M. P.; Capron, C.; Ledgerwood, E. C.: A mutation of human
cytochrome c enhances the intrinsic apoptotic pathway but causes only
thrombocytopenia. Nature Genet. 40: 387-389, 2008.

11. Zhang, Z.; Gerstein, M.: The human genome has 49 cytochrome c
pseudogenes, including a relic of a primordial gene that still functions
in mouse. Gene 312: 61-72, 2003.

*FIELD* CN
Matthew B. Gross - updated: 4/29/2010
Patricia A. Hartz - updated: 10/24/2008
Ada Hamosh - updated: 4/23/2008
Patricia A. Hartz - updated: 2/9/2004
Stylianos E. Antonarakis - updated: 6/7/2000
Ada Hamosh - updated: 2/5/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 11/26/2012
carol: 3/28/2012
alopez: 3/7/2012
carol: 8/26/2011
wwang: 5/4/2010
mgross: 4/29/2010
mgross: 10/24/2008
alopez: 6/6/2008
alopez: 4/23/2008
terry: 4/23/2008
carol: 3/31/2004
mgross: 2/9/2004
alopez: 9/30/2003
mgross: 6/7/2000
alopez: 2/5/1999
davew: 8/5/1994
warfield: 2/14/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 1/13/1989

MIM 612004
*RECORD*
*FIELD* NO
612004
*FIELD* TI
#612004 THROMBOCYTOPENIA 4; THC4
;;THROMBOCYTOPENIA, AUTOSOMAL DOMINANT, 4
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that a
form of autosomal dominant nonsyndromic thrombocytopenia is due to a
mutation in cytochrome c (CYCS; 123970).

For a phenotypic description and a discussion of genetic heterogeneity
of thrombocytopenia, see 313900.

CLINICAL FEATURES

Morison et al. (2008) described a 6-generation pedigree segregating
autosomal dominant thrombocytopenia. Affected individuals had platelet
counts ranging from 73 to 167 with a reference interval of 150 to 430.
Clinical manifestations of thrombocytopenia were absent or mild.
Affected individuals had normal longevity, fertility, and fitness with
no evidence of neurodegenerative, muscular, eye, or kidney disease, or
diabetes.

MOLECULAR GENETICS

Morison et al. (2008) identified a G-to-A transition at nucleotide 132
in exon 2 of the gene encoding cytochrome c (CYCS; 123970.0001) that
caused a substitution of glycine by serine at codon 41 (G41S).
Cytochrome c is a highly conserved protein, and glycine-41 is invariant
among 113 eukaryotic species. Peripheral blood from affected family
members contained the same proportion of immature platelets as controls,
indicating no reduction of platelet life span. However, the absolute
number of immature platelets was lower, suggesting reduced production.
Bone marrow from a 76-year-old affected individual showed intramedullary
naked megakaryocyte nuclei and platelets, suggesting dysregulated
megakaryopoiesis with premature release of platelets into the marrow
space rather than into sinusoids.

*FIELD* RF
1. Morison, I. M.; Borde, E. M. C.; Cheesman, E. J.; Cheong, P. L.;
Holyoake, A. J.; Fichelson, S.; Weeks, R. J.; Lo, A.; Davies, S. M.
K.; Wilbanks, S. M.; Fagerlund, R. D.; Ludgate, M. W.; da Silva Tatley,
F. M.; Coker, M. S. A.; Bockett, N. A.; Hughes, G.; Pippig, D. A.;
Smith, M. P.; Capron, C.; Ledgerwood, E. C.: A mutation of human
cytochrome c enhances the intrinsic apoptotic pathway but causes only
thrombocytopenia. Nature Genet. 40: 387-389, 2008.

*FIELD* CD
Ada Hamosh: 4/23/2008

*FIELD* ED
alopez: 04/23/2008

RBCC Red Blood Cell Collection

Full text data of CYCS