Reviewed, UniProtKB/Swiss-Prot P99999 (CYC_HUMAN)

Names and origin

Protein names

Recommended name:
    Cytochrome c

Gene names

Name:	CYCS
Synonyms:	CYC

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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 matrix.
Post-translational modification	Binds 1 heme group per subunit.
Involvement in disease	Defects in CYCS are the cause of thrombocytopenia type 4 (THC4) [MIM:612004]; also known as autosomal dominant thrombocytopenia type 4. Thrombocytopenia is the presence of relatively few platelets in blood. THC4 is a non-syndromic form of thrombocytopenia. Clinical manifestations of thrombocytopenia are absent or mild. THC4 may be caused by dysregulated platelet formation.
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
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	DNA fragmentation during apoptosis Inferred from mutant phenotype. Source: UniProtKB caspase activation via cytochrome c Traceable author statement. Source: UniProtKB cellular respiration Traceable author statement. Source: UniProtKB
Cellular component	cytosol Inferred from mutant phenotype. Source: UniProtKB mitochondrial intermembrane space Traceable author statement. Source: UniProtKB nucleus Inferred from direct assay. Source: LIFEdb protein phosphatase type 2A complex Traceable author statement. Source: UniProtKB
Molecular function	electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity Inferred from direct assay. Source: UniProtKB heme binding Ref.9 Traceable author statement. Source: UniProtKB protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APAF1	O14727	2	EBI-446479,EBI-446492
GSTK1	Q9Y2Q3	1	EBI-446479,EBI-1053767

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

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

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.

VAR_044450

Natural variant

66

1

M → L in 10% of the molecules.

VAR_002204

Experimental info

Sequence conflict

18

1

C → Y in AAH15130. Ref.6

Sequence conflict

41

1

T → I in AAH68464. Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

105

Helix Strand Turn

Details...

Helix

4 – 14

11

Turn

16 – 18

3

Beta strand

23 – 25

3

Beta strand

28 – 30

3

Turn

36 – 38

3

Helix

51 – 56

6

Helix

62 – 70

9

Helix

72 – 75

4

Helix

89 – 102

14

Sequences

	Sequence		Length	Mass (Da)
	P99999-1 [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: 2849112] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	The German cDNA consortium Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Amygdala.
[3]	"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].
[4]	"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: 12853948] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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: 12690205] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone marrow, Brain, Kidney, Lung, Skeletal muscle, Skin, Testis and Urinary bladder.
[7]	"The amino acid sequence of human heart cytochrome c." Matsubara H., Smith E.L. J. Biol. Chem. 237:3575-3576(1962) [PubMed: 13933734] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-105, ACETYLATION AT GLY-2. Tissue: Heart.
[8]	"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: 14063298] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-105. Tissue: Heart.
[9]	"Cytochrome c in the apoptotic and antioxidant cascades." Skulachev V.P. FEBS Lett. 423:275-280(1998) [PubMed: 9515723] [Abstract] Cited for: REVIEW ON ROLE IN APOPTOSIS.
[10]	"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.
[11]	"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: 18345000] [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

EMBLGenBankDDBJ

M22877 Genomic DNA. Translation: AAA35732.1.
AL713681 mRNA. Translation: CAD28485.1.
BT006946 mRNA. Translation: AAP35592.1.
AC007487 Genomic DNA. Translation: AAQ96844.1.
CH236948 Genomic DNA. Translation: EAL24239.1.
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.

PIR

CCHU. A31764.

RefSeq

NP_061820.1.

UniGene

Hs.437060
Hs.617193

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1J3S	NMR	-	A	1-105	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P99999.

PTM databases

PhosphoSite

P99999.

Proteomic databases

PeptideAtlas

P99999.

Genome annotation databases

Ensembl

ENSG00000172115. Homo sapiens. [Contig view]

GeneID

54205.

KEGG

hsa:54205.

Organism-specific databases

H-InvDB

HIX0006529.

HGNC

HGNC:19986. CYCS.

HPA

CAB005126.
CAB018597.

MIM

123970. gene.
612004. phenotype.

PharmGKB

PA134981636.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

P99999.

HOVERGEN

P99999.

Enzyme and pathway databases

Reactome

REACT_578. Apoptosis.
REACT_6305. Electron Transport Chain.

Gene expression databases

ArrayExpress

P99999.

CleanEx

HS_CYCS.

GermOnline

ENSG00000172115. Homo sapiens.

Family and domain databases

InterPro

IPR009056. Cyt_c_monohaem.
IPR003088. Cyt_CI.
IPR002327. Cyt_CIAB.
[Graphical view]

Gene3D

G3DSA:1.10.760.10. Cytochrome_c_R. 1 hit.

PANTHER

PTHR11961. Cyt_CIAB. 1 hit.

Pfam

PF00034. Cytochrom_C. 1 hit.
[Graphical view]

PRINTS

PR00604. CYTCHRMECIAB.

ProDom

PD000375. Cyt_CIAB. 1 hit.
[Graphical view] [Entries sharing at least one domain]

PROSITE

PS51007. CYTC. 1 hit.
[Graphical view]

BLOCKS

Search...

ProtoNet

Search...

Other Resources

DrugBank

DB01065. Melatonin.
DB01017. Minocycline.

LinkHub

P99999.

NextBio

56526.

SOURCE

Search...

Entry information

Entry name

CYC_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	January 23, 2007
Last modified:	November 4, 2008
This is version 66 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)