P30405 (PPIF_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Short name=PPIase F
EC=5.2.1.8

Alternative name(s):
Cyclophilin D
Short name=CyP-D
Short name=CypD
Cyclophilin F
Mitochondrial cyclophilin
Short name=CyP-M
Rotamase F

Gene names

Name:	PPIF
Synonyms:	CYP3

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 › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	207 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	PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probablity of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F1F0 ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis. Ref.5 Ref.9
Catalytic activity	Peptidylproline (omega=180) = peptidylproline (omega=0).
Enzyme regulation	Binds cyclosporin A (CsA). Is displaced by CsA from the mPTP leading to a lower open probablity of the mPTP.
Subunit structure	Believed to associate with the mitochondrial permeability transition pore complex (PTPC). Associates with the mitochondrial membrane ATP synthase F1F0 ATP synthase; the association is increased by inorganic phosphate (Pi) and decreased by cyclosporin A (CsA). Interacts with ATP5B; ATP5H and ATP5O. Interacts with SLC25A3; the interaction is impaired by CsA. Interacts with BCL2; the interaction is impaired by CsA. Interacts with TP53; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by CsA. Interacts with C1QBP. Ref.5 Ref.7 Ref.9
Subcellular location	Mitochondrion matrix Ref.4.
Post-translational modification	Deacteylated at Lys-167 by SIRT3 By similarity.
Sequence similarities	Belongs to the cyclophilin-type PPIase family. Contains 1 PPIase cyclophilin-type domain.

Ontologies

Keywords
Biological process	Apoptosis Necrosis
Cellular component	Mitochondrion
Domain	Transit peptide
Ligand	Cyclosporin
Molecular function	Isomerase Rotamase
PTM	Acetylation S-nitrosylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic mitochondrial changes Inferred from electronic annotation. Source: Ensembl cellular response to arsenic-containing substance Inferred from sequence or structural similarity. Source: UniProtKB cellular response to calcium ion Inferred from sequence or structural similarity. Source: UniProtKB cellular response to hydrogen peroxide Inferred from mutant phenotype Ref.9. Source: UniProtKB negative regulation of ATPase activity Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from direct assay Ref.5. Source: UniProtKB negative regulation of intrinsic apoptotic signaling pathway Inferred from mutant phenotype Ref.5. Source: UniProtKB negative regulation of oxidative phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of oxidative phosphorylation uncoupler activity Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of release of cytochrome c from mitochondria Inferred from direct assay Ref.5. Source: UniProtKB positive regulation of necrotic cell death Inferred from electronic annotation. Source: Ensembl positive regulation of release of cytochrome c from mitochondria Inferred from sequence or structural similarity. Source: UniProtKB protein folding Inferred from electronic annotation. Source: UniProtKB-KW regulation of mitochondrial membrane permeability Inferred from sequence or structural similarity. Source: UniProtKB regulation of mitochondrial membrane permeability involved in programmed necrotic cell death Inferred from mutant phenotype Ref.9. Source: UniProtKB regulation of proton-transporting ATPase activity, rotational mechanism Inferred from sequence or structural similarity. Source: UniProtKB response to ischemia Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	membrane Traceable author statement Ref.1. Source: ProtInc mitochondrial inner membrane Inferred from electronic annotation. Source: Ensembl mitochondrial matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	cyclosporin A binding Inferred from electronic annotation. Source: Ensembl peptidyl-prolyl cis-trans isomerase activity Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction Ref.9. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TP53	P04637	4	EBI-5544229,EBI-366083

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 29

29

Mitochondrion Potential

Chain

30 – 207

178

Peptidyl-prolyl cis-trans isomerase F, mitochondrial

PRO_0000025489

Regions

Domain

49 – 205

157

PPIase cyclophilin-type

Amino acid modifications

Modified residue

67

1

N6-acetyllysine; alternate By similarity

Modified residue

67

1

N6-succinyllysine; alternate By similarity

Modified residue

86

1

N6-succinyllysine By similarity

Modified residue

167

1

N6-acetyllysine By similarity

Modified residue

175

1

N6-succinyllysine By similarity

Modified residue

190

1

N6-succinyllysine By similarity

Modified residue

203

1

S-nitrosocysteine By similarity

Experimental info

Mutagenesis

203

1

C → S: Blocks Ca(2+)-induced mPTP opening and reduces hydrogen peroxide-induced cell death. Ref.8

Secondary structure

1

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207

Helix Strand Turn

Details...

Beta strand

47 – 54

8

Beta strand

57 – 66

10

Turn

68 – 70

3

Helix

72 – 83

12

Turn

84 – 86

3

Beta strand

94 – 99

6

Turn

100 – 102

3

Beta strand

103 – 106

4

Turn

109 – 111

3

Beta strand

112 – 115

4

Beta strand

120 – 123

4

Beta strand

139 – 142

4

Beta strand

144 – 146

3

Beta strand

150 – 152

3

Beta strand

154 – 159

6

Helix

162 – 164

3

Turn

165 – 167

3

Beta strand

170 – 176

7

Helix

178 – 186

9

Beta strand

198 – 205

8

Sequences

	Sequence		Length	Mass (Da)
	P30405 [UniParc]. Last modified April 1, 1993. Version 1. Checksum: D7C76F1D4049F16A	FASTA	207	22,040
	10 20 30 40 50 60 MLALRCGSRW LGLLSVPRSV PLRLPAARAC SKGSGDPSSS SSSGNPLVYL DVDANGKPLG 70 80 90 100 110 120 RVVLELKADV VPKTAENFRA LCTGEKGFGY KGSTFHRVIP SFMCQAGDFT NHNGTGGKSI 130 140 150 160 170 180 YGSRFPDENF TLKHVGPGVL SMANAGPNTN GSQFFICTIK TDWLDGKHVV FGHVKEGMDV 190 200 VKKIESFGSK SGRTSKKIVI TDCGQLS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The cyclophilin multigene family of peptidyl-prolyl isomerases. Characterization of three separate human isoforms." Bergsma D.J., Eder C., Gross M., Kersten H., Sylvester D., Appelbaum E., Cusimano D., Livi G.P., McLauglin M.M., Kasyan K., Porter T.G., Silverman C., Dunnington D., Hand A., Prichett W.P., Bossard M.J., Brandt M., Levy M.A. J. Biol. Chem. 266:23204-23214(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"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: Ovary.
[4]	"Import and processing of heart mitochondrial cyclophilin D." Johnson N., Khan A., Virji S., Ward J.M., Crompton M. Eur. J. Biochem. 263:353-359(1999) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[5]	"Cyclophilin D interacts with Bcl2 and exerts an anti-apoptotic effect." Eliseev R.A., Malecki J., Lester T., Zhang Y., Humphrey J., Gunter T.E. J. Biol. Chem. 284:9692-9699(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH BCL2.
[6]	"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].
[7]	"Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death." McGee A.M., Baines C.P. Biochem. J. 433:119-125(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH C1QBP.
[8]	"Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of the mitochondrial permeability transition pore." Nguyen T.T., Stevens M.V., Kohr M., Steenbergen C., Sack M.N., Murphy E. J. Biol. Chem. 286:40184-40192(2011) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF CYS-203.
[9]	"p53 opens the mitochondrial permeability transition pore to trigger necrosis." Vaseva A.V., Marchenko N.D., Ji K., Tsirka S.E., Holzmann S., Moll U.M. Cell 149:1536-1548(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TP53.
[10]	"Crystal engineering yields crystals of cyclophilin D diffracting to 1.7 A resolution." Schlatter D., Thoma R., Kung E., Stihle M., Muller F., Borroni E., Cesura A., Hennig M. Acta Crystallogr. D 61:513-519(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.71 ANGSTROMS) OF 43-207.
[11]	"Crystal structure of human cyclophilin D in complex with its inhibitor, cyclosporin A at 0.96-A resolution." Kajitani K., Fujihashi M., Kobayashi Y., Shimizu S., Tsujimoto Y., Miki K. Proteins 70:1635-1639(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (0.96 ANGSTROMS) OF 44-207 IN COMPLEX WITH CYCLOSPORIN A.
[12]	"In-plate protein crystallization, in situ ligand soaking and X-ray diffraction." le Maire A., Gelin M., Pochet S., Hoh F., Pirocchi M., Guichou J.F., Ferrer J.L., Labesse G. Acta Crystallogr. D 67:747-755(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS) OF 44-207.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M80254 mRNA. Translation: AAA58434.1.
AL133481, AL391665 Genomic DNA. Translation: CAH72725.1.
AL391665, AL133481 Genomic DNA. Translation: CAI40994.1.
BC005020 mRNA. Translation: AAH05020.1.

CCDS

CCDS7358.1.

PIR

A41581.

RefSeq

NP_005720.1. NM_005729.3.

UniGene

Hs.381072.

3D structure databases

PDBe
RCSB-PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2BIT	X-ray	1.71	X	43-207	[»]
2BIU	X-ray	1.71	X	43-207	[»]
2Z6W	X-ray	0.96	A/B	44-207	[»]
3QYU	X-ray	1.54	A	44-207	[»]
3R49	X-ray	1.77	A	43-207	[»]
3R4G	X-ray	1.05	A	43-207	[»]
3R54	X-ray	1.35	A	43-207	[»]
3R56	X-ray	1.40	A	43-207	[»]
3R57	X-ray	1.71	A	43-207	[»]
3R59	X-ray	1.10	A	43-207	[»]
3RCF	X-ray	1.15	A	43-207	[»]
3RCG	X-ray	0.97	A	43-207	[»]
3RCI	X-ray	1.44	X	43-207	[»]
3RCK	X-ray	1.26	X	43-207	[»]
3RCL	X-ray	1.70	A	43-207	[»]
3RD9	X-ray	1.40	X	43-207	[»]
3RDA	X-ray	1.07	X	43-207	[»]
3RDB	X-ray	1.55	A	43-207	[»]
3RDC	X-ray	1.94	A	43-207	[»]
4J58	X-ray	1.28	A	44-207	[»]
4J59	X-ray	1.92	A	44-207	[»]
4J5A	X-ray	1.58	X	44-207	[»]
4J5B	X-ray	2.01	A	44-207	[»]
4J5C	X-ray	1.03	X	44-207	[»]
4J5D	X-ray	1.32	X	44-207	[»]
4J5E	X-ray	0.99	X	44-207	[»]

ProteinModelPortal

P30405.

SMR

P30405. Positions 44-207.

ModBase

Search...

MobiDB

Search...

Protein-protein interaction databases

BioGrid

115411. 24 interactions.

IntAct

P30405. 5 interactions.

MINT

MINT-3011711.

STRING

9606.ENSP00000225174.

Chemistry

DrugBank

DB01093. Dimethyl sulfoxide.
DB00172. L-Proline.

PTM databases

PhosphoSite

P30405.

Polymorphism databases

DMDM

231968.

2D gel databases

OGP

P30405.

UCD-2DPAGE

P30405.

Proteomic databases

MaxQB

P30405.

PaxDb

P30405.

PeptideAtlas

P30405.

PRIDE

P30405.

Protocols and materials databases

DNASU

10105.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000225174; ENSP00000225174; ENSG00000108179.

GeneID

10105.

KEGG

hsa:10105.

UCSC

uc001kai.3. human.

Organism-specific databases

CTD

10105.

GeneCards

GC10P081107.

HGNC

HGNC:9259. PPIF.

MIM

604486. gene.

neXtProt

NX_P30405.

PharmGKB

PA33584.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0652.

HOGENOM

HOG000065981.

HOVERGEN

HBG001065.

InParanoid

P30405.

KO

K09565.

OMA

AFMCQAG.

OrthoDB

EOG79GT7W.

PhylomeDB

P30405.

TreeFam

TF312801.

Gene expression databases

ArrayExpress

P30405.

Bgee

P30405.

CleanEx

HS_PPIF.

Genevestigator

P30405.

Family and domain databases

Gene3D

2.40.100.10. 1 hit.

InterPro

IPR029000. Cyclophilin-like_dom.
IPR024936. Cyclophilin-type_PPIase.
IPR020892. Cyclophilin-type_PPIase_CS.
IPR002130. Cyclophilin-type_PPIase_dom.
[Graphical view]

Pfam

PF00160. Pro_isomerase. 1 hit.
[Graphical view]

PIRSF

PIRSF001467. Peptidylpro_ismrse. 1 hit.

PRINTS

PR00153. CSAPPISMRASE.

SUPFAM

SSF50891. SSF50891. 1 hit.

PROSITE

PS00170. CSA_PPIASE_1. 1 hit.
PS50072. CSA_PPIASE_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

PPIF. human.

EvolutionaryTrace

P30405.

GeneWiki

PPIF.

GenomeRNAi

10105.

NextBio

38221.

PRO

P30405.

SOURCE

Search...

Entry information

Entry name

PPIF_HUMAN

Accession

Primary (citable) accession number: P30405
Secondary accession number(s): Q5W131

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	July 9, 2014
This is version 136 of the entry and version 1 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.