Q99KR7 (PPIF_MOUSE) 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
Rotamase F

Gene names

Name:

Ppif

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	206 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.2 Ref.3 Ref.4 Ref.5 Ref.6 Ref.9 Ref.11
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.7 Ref.8 Ref.9 Ref.11
Subcellular location	Mitochondrion matrix By similarity.
Post-translational modification	Deacteylated at Lys-166 by SIRT3.
Disruption phenotype	Mice are developmentally normal and show no apparent anomalies. Mitochondria do not undergo cyclosporin A-sensitive mitochondrial permeability transtition. Cells show resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload, and animals show a high level of resistance to ischaemia/reperfusion-induced cardiac injury. Mice show a dramatic reduction in brain infarct size after acute middle cerebral artery occlusion and reperfusion. Ref.2 Ref.3 Ref.4
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	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic mitochondrial changes Inferred from genetic interaction PubMed 18350175. Source: MGI cellular response to arsenic-containing substance Inferred from mutant phenotype Ref.9. Source: UniProtKB cellular response to calcium ion Inferred from mutant phenotype Ref.2Ref.3Ref.4. Source: UniProtKB cellular response to hydrogen peroxide Inferred from mutant phenotype Ref.2Ref.3Ref.4Ref.11. Source: UniProtKB negative regulation of ATPase activity Inferred from mutant phenotype Ref.9. Source: UniProtKB negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of intrinsic apoptotic signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of oxidative phosphorylation Inferred from mutant phenotype Ref.9. Source: UniProtKB negative regulation of oxidative phosphorylation uncoupler activity Inferred from mutant phenotype Ref.9. Source: UniProtKB negative regulation of release of cytochrome c from mitochondria Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of necrotic cell death Inferred from mutant phenotype Ref.2Ref.4Ref.11. Source: UniProtKB positive regulation of release of cytochrome c from mitochondria Inferred from mutant phenotype Ref.3. Source: UniProtKB protein folding Inferred from electronic annotation. Source: UniProtKB-KW regulation of mitochondrial membrane permeability Inferred from mutant phenotype Ref.4Ref.5. Source: UniProtKB regulation of proton-transporting ATPase activity, rotational mechanism Inferred from mutant phenotype Ref.6Ref.9. Source: UniProtKB response to ischemia Inferred from mutant phenotype Ref.2Ref.4. Source: UniProtKB
Cellular_component	mitochondrial inner membrane Inferred from electronic annotation. Source: Compara mitochondrial matrix Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrion Inferred from direct assay PubMed 14651853PubMed 18614015. Source: MGI
Molecular_function	cyclosporin A binding Inferred from electronic annotation. Source: Compara peptidyl-prolyl cis-trans isomerase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Tp53	P02340	2	EBI-6455001,EBI-474016

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 29	29	Mitochondrion By similarity
	Chain	30 – 206	177	Peptidyl-prolyl cis-trans isomerase F, mitochondrial		PRO_0000025490
Regions
	Domain	48 – 204	157	PPIase cyclophilin-type
Amino acid modifications
	Modified residue	166	1	N6-acetyllysine Ref.7
	Modified residue	202	1	S-nitrosocysteine Ref.10

Sequences

	Sequence		Length	Mass (Da)
	Q99KR7 [UniParc]. Last modified June 1, 2001. Version 1. Checksum: 6E6BFE4D6B064D6F	FASTA	206	21,737
	10 20 30 40 50 60 MLALRCGPRL LGLLSGPRSA PLLLSATRTC SDGGARGANS SSGNPLVYLD VGADGQPLGR 70 80 90 100 110 120 VVLELKADVV PKTAENFRAL CTGEKGFGYK GSTFHRVIPA FMCQAGDFTN HNGTGGRSIY 130 140 150 160 170 180 GSRFPDENFT LKHVGPGVLS MANAGPNTNG SQFFICTIKT DWLDGKHVVF GHVKEGMDVV 190 200 KKIESFGSKS GKTSKKIVIT DCGQLS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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: Mammary tumor.
[2]	"Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death." Nakagawa T., Shimizu S., Watanabe T., Yamaguchi O., Otsu K., Yamagata H., Inohara H., Kubo T., Tsujimoto Y. Nature 434:652-658(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[3]	"Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death." Baines C.P., Kaiser R.A., Purcell N.H., Blair N.S., Osinska H., Hambleton M.A., Brunskill E.W., Sayen M.R., Gottlieb R.A., Dorn G.W., Robbins J., Molkentin J.D. Nature 434:658-662(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[4]	"Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia." Schinzel A.C., Takeuchi O., Huang Z., Fisher J.K., Zhou Z., Rubens J., Hetz C., Danial N.N., Moskowitz M.A., Korsmeyer S.J. Proc. Natl. Acad. Sci. U.S.A. 102:12005-12010(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[5]	"Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation." Basso E., Petronilli V., Forte M.A., Bernardi P. J. Biol. Chem. 283:26307-26311(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex." Giorgio V., Bisetto E., Soriano M.E., Dabbeni-Sala F., Basso E., Petronilli V., Forte M.A., Bernardi P., Lippe G. J. Biol. Chem. 284:33982-33988(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy." Hafner A.V., Dai J., Gomes A.P., Xiao C.Y., Palmeira C.M., Rosenzweig A., Sinclair D.A. Aging (Albany NY) 2:914-923(2010) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION AT LYS-166, INTERACTION WITH SIRT3.
[8]	"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.
[9]	"Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels." Chinopoulos C., Konrad C., Kiss G., Metelkin E., Torocsik B., Zhang S.F., Starkov A.A. FEBS J. 278:1112-1125(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ATP5B.
[10]	"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: S-NITROSYLATION AT CYS-202.
[11]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	BC004041 mRNA. Translation: AAH04041.1.
IPI	IPI00116228.
RefSeq	NP_598845.1. NM_134084.1.
UniGene	Mm.41656.
3D structure databases
ProteinModelPortal	Q99KR7.
SMR	Q99KR7. Positions 43-206.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q99KR7. 4 interactions.
STRING	10090.ENSMUSP00000022419.
PTM databases
PhosphoSite	Q99KR7.
Proteomic databases
PaxDb	Q99KR7.
PRIDE	Q99KR7.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000022419; ENSMUSP00000022419; ENSMUSG00000021868.
GeneID	105675.
KEGG	mmu:105675.
UCSC	uc007srr.1. mouse.
Organism-specific databases
CTD	10105.
MGI	MGI:2145814. Ppif.
Phylogenomic databases
eggNOG	COG0652.
GeneTree	ENSGT00690000101651.
HOGENOM	HOG000065981.
HOVERGEN	HBG001065.
InParanoid	Q99KR7.
KO	K09565.
OMA	ESIYGHK.
OrthoDB	EOG4DJJXN.
Gene expression databases
Bgee	Q99KR7.
CleanEx	MM_PPIF.
Genevestigator	Q99KR7.
Family and domain databases
InterPro	IPR002130. Cyclophilin-like_PPIase_dom. IPR024936. Cyclophilin-type_PPIase. IPR020892. Cyclophilin-type_PPIase_CS. [Graphical view]
Pfam	PF00160. Pro_isomerase. 1 hit. [Graphical view]
PIRSF	PIRSF001467. Peptidylpro_ismrse. 1 hit.
PRINTS	PR00153. CSAPPISMRASE.
SUPFAM	SSF50891. CSA_PPIase. 1 hit.
PROSITE	PS00170. CSA_PPIASE_1. 1 hit. PS50072. CSA_PPIASE_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	357826.
SOURCE	Search...

Entry information

Entry name

PPIF_MOUSE

Accession

Primary (citable) accession number: Q99KR7

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 11, 2002
Last sequence update:	June 1, 2001
Last modified:	April 3, 2013
This is version 84 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program