P99999 (CYC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cytochrome c

Gene names

Name:	CYCS
Synonyms:	CYC

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	105 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain. Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases.
Subcellular location	Mitochondrion intermembrane space. Note: Loosely associated with the inner membrane.
Post-translational modification	Binds 1 heme group per subunit. Phosphorylation at Tyr-49 and Tyr-98 both reduce by half the turnover in the reaction with cytochrome c oxidase, down-regulating mitochondrial respiration By similarity.
Involvement in disease	Thrombocytopenia 4 (THC4) [MIM:612004]: Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.15
Sequence similarities	Belongs to the cytochrome c family.

Ontologies

Keywords
Biological process	Apoptosis Electron transport Respiratory chain Transport
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	Heme Iron Metal-binding
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c Traceable author statement PubMed 9267021. Source: UniProtKB apoptotic DNA fragmentation Inferred from mutant phenotype PubMed 8689682. Source: UniProtKB respiratory electron transport chain Traceable author statement. Source: Reactome small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Inferred from mutant phenotype PubMed 8689682. Source: UniProtKB mitochondrial inner membrane Traceable author statement. Source: Reactome mitochondrial intermembrane space Traceable author statement PubMed 8689682. Source: UniProtKB nucleus Inferred from direct assay. Source: LIFEdb protein phosphatase type 2A complex Traceable author statement PubMed 8206937. Source: UniProtKB respiratory chain Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity Inferred from direct assay PubMed 8689682. Source: UniProtKB heme binding Traceable author statement Ref.11. Source: UniProtKB iron ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APAF1	O14727	6	EBI-446479,EBI-446492

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.9 Ref.10

Chain

2 – 105

104

Cytochrome c

PRO_0000108218

Sites

Metal binding

19

1

Iron (heme axial ligand)

Metal binding

81

1

Iron (heme axial ligand)

Binding site

15

1

Heme (covalent)

Binding site

18

1

Heme (covalent)

Amino acid modifications

Modified residue

2

1

N-acetylglycine Ref.9

Modified residue

49

1

Phosphotyrosine By similarity

Modified residue

98

1

Phosphotyrosine By similarity

Natural variations

Natural variant

42

1

G → S in THC4; increases the pro-apoptotic function by triggering caspase activation more efficiently than wild-type; does not affect the redox function. Ref.15

VAR_044450

Natural variant

56

1

K → R.
Corresponds to variant rs11548795 [ dbSNP | Ensembl ].

VAR_048850

Natural variant

66

1

M → L in 10% of the molecules.

VAR_002204

Experimental info

Sequence conflict

18

1

C → Y in AAH15130. Ref.8

Sequence conflict

41

1

T → I in AAH68464. Ref.8

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

105

Helix Strand Turn

Details...

Helix

4 – 14

11

Turn

15 – 18

4

Beta strand

23 – 25

3

Beta strand

28 – 30

3

Turn

36 – 38

3

Helix

51 – 55

5

Helix

62 – 70

9

Helix

72 – 75

4

Helix

89 – 102

14

Sequences

	Sequence		Length	Mass (Da)
	P99999 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 8EE9689E0102506B	FASTA	105	11,749
	10 20 30 40 50 60 MGDVEKGKKI FIMKCSQCHT VEKGGKHKTG PNLHGLFGRK TGQAPGYSYT AANKNKGIIW 70 80 90 100 GEDTLMEYLE NPKKYIPGTK MIFVGIKKKE ERADLIAYLK KATNE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The human somatic cytochrome c gene: two classes of processed pseudogenes demarcate a period of rapid molecular evolution." Evans M.J., Scarpulla R.C. Proc. Natl. Acad. Sci. U.S.A. 85:9625-9629(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cerebellum.
[4]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Amygdala.
[5]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"Human chromosome 7: DNA sequence and biology." Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., Kanematsu E., Gentles S. , Christopoulos C.C., Choufani S., Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., Adams M.D., Tsui L.-C. Science 300:767-772(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone marrow, Brain, Kidney, Lung, Skeletal muscle, Skin, Testis and Urinary bladder.
[9]	"The amino acid sequence of human heart cytochrome c." Matsubara H., Smith E.L. J. Biol. Chem. 237:3575-3576(1962) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-105, ACETYLATION AT GLY-2. Tissue: Heart.
[10]	"Human heart cytochrome c. Chymotryptic peptides, tryptic peptides, and the complete amino acid sequence." Matsubara H., Smith E.L. J. Biol. Chem. 238:2732-2753(1963) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-105. Tissue: Heart.
[11]	"Cytochrome c in the apoptotic and antioxidant cascades." Skulachev V.P. FEBS Lett. 423:275-280(1998) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON ROLE IN APOPTOSIS.
[12]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]	"Solution structure of reduced recombinant human cytochrome c." Jeng W.-Y., Shiu J.-H., Tsai Y.-H., Chuang W.-J. Submitted (FEB-2003) to the PDB data bank Cited for: STRUCTURE BY NMR.
[15]	"A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia." Morison I.M., Cramer 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. Nat. Genet. 40:387-389(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THC4 SER-42, MASS SPECTROMETRY, CHARACTERIZATION OF VARIANT THC4 SER-42, X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF VARIANT THC4 SER-42 AND WILD TYPE.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

Life shuttle - Issue 76 of November 2006

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M22877 Genomic DNA. Translation: AAA35732.1.
BT006946 mRNA. Translation: AAP35592.1.
AK311836 mRNA. Translation: BAG34778.1.
AL713681 mRNA. Translation: CAD28485.1.
AC007487 Genomic DNA. Translation: AAQ96844.1.
CH236948 Genomic DNA. Translation: EAL24239.1.
CH471073 Genomic DNA. Translation: EAW93822.1.
BC005299 mRNA. Translation: AAH05299.1.
BC008475 mRNA. Translation: AAH08475.1.
BC008477 mRNA. Translation: AAH08477.1.
BC009578 mRNA. Translation: AAH09578.1.
BC009579 mRNA. Translation: AAH09579.1.
BC009582 mRNA. Translation: AAH09582.1.
BC009587 mRNA. Translation: AAH09587.1.
BC009602 mRNA. Translation: AAH09602.1.
BC009607 mRNA. Translation: AAH09607.1.
BC014359 mRNA. Translation: AAH14359.1.
BC014361 mRNA. Translation: AAH14361.1.
BC015130 mRNA. Translation: AAH15130.1.
BC016006 mRNA. Translation: AAH16006.1.
BC021994 mRNA. Translation: AAH21994.1.
BC022330 mRNA. Translation: AAH22330.1.
BC067222 mRNA. Translation: AAH67222.1.
BC068464 mRNA. Translation: AAH68464.1.
BC070156 mRNA. Translation: AAH70156.1.
BC070346 mRNA. Translation: AAH70346.1.
BC071761 mRNA. Translation: AAH71761.1.

IPI

IPI00465315.

PIR

CCHU. A31764.

RefSeq

NP_061820.1. NM_018947.5.

UniGene

Hs.437060.
Hs.617193.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1J3S	NMR	-	A	2-104	[»]
3NWV	X-ray	1.90	A/B/C/D	2-105	[»]

ProteinModelPortal

P99999.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29683N.

IntAct

P99999. 5 interactions.

STRING

9606.ENSP00000307786.

PTM databases

PhosphoSite

P99999.

Polymorphism databases

DMDM

42560196.

Proteomic databases

PaxDb

P99999.

PeptideAtlas

P99999.

PRIDE

P99999.

Protocols and materials databases

DNASU

54205.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000305786; ENSP00000307786; ENSG00000172115.
ENST00000409409; ENSP00000386270; ENSG00000172115.
ENST00000409764; ENSP00000387279; ENSG00000172115.

GeneID

54205.

KEGG

hsa:54205.

UCSC

uc003sxl.3. human.

Organism-specific databases

CTD

54205.

GeneCards

GC07M025124.

HGNC

HGNC:19986. CYCS.

HPA

CAB004222.
CAB005126.
CAB018597.

MIM

123970. gene.
612004. phenotype.

neXtProt

NX_P99999.

Orphanet

168629. Autosomal thrombocytopenia with normal platelets.

PharmGKB

PA134981636.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG3474.

HOGENOM

HOG000009762.

HOVERGEN

HBG003023.

InParanoid

P99999.

KO

K08738.

OMA

KMIYAGL.

OrthoDB

EOG45DWQX.

PhylomeDB

P99999.

Enzyme and pathway databases

Pathway_Interaction_DB

caspase_pathway. Caspase cascade in apoptosis.
ceramidepathway. Ceramide signaling pathway.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
p75ntrpathway. p75(NTR)-mediated signaling.

Reactome

REACT_111217. Metabolism.
REACT_578. Apoptosis.

Gene expression databases

ArrayExpress

P99999.

Bgee

P99999.

CleanEx

HS_CYCS.

Genevestigator

P99999.

GermOnline

ENSG00000172115. Homo sapiens.

Family and domain databases

InterPro

IPR002327. Cyt_c_1A/1B.
IPR009056. Cyt_c_dom.
IPR003088. Cyt_c_I.
[Graphical view]

PANTHER

PTHR11961. PTHR11961. 1 hit.

Pfam

PF00034. Cytochrom_C. 1 hit.
[Graphical view]

PRINTS

PR00604. CYTCHRMECIAB.

SUPFAM

SSF46626. Cytochrome_c. 1 hit.

PROSITE

PS51007. CYTC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

CYCS. human.

DrugBank

DB01065. Melatonin.
DB01017. Minocycline.

EvolutionaryTrace

P99999.

GenomeRNAi

54205.

NextBio

56526.

SOURCE

Search...

Entry information

Entry name

CYC_HUMAN

Accession

Primary (citable) accession number: P99999
Secondary accession number(s): A4D166 , B2R4I1, P00001, Q6NUR2, Q6NX69, Q96BV4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 113 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.