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Q99KR7 (PPIF_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 96. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length206 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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 processApoptosis
Necrosis
   Cellular componentMitochondrion
   DomainTransit peptide
   LigandCyclosporin
   Molecular functionIsomerase
Rotamase
   PTMAcetylation
S-nitrosylation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processapoptotic 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

necroptotic process

Inferred from genetic interaction Ref.11. Source: MGI

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 electronic annotation. Source: Ensembl

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

protein peptidyl-prolyl isomerization

Traceable author statement PubMed 18309324. Source: UniProtKB

regulation of mitochondrial membrane permeability

Inferred from mutant phenotype Ref.4Ref.5. Source: UniProtKB

regulation of mitochondrial membrane permeability involved in programmed necrotic cell death

Inferred from mutant phenotype Ref.2Ref.4Ref.11. Source: UniProtKB

regulation of necrotic cell death

Inferred from direct assay Ref.3. 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

response to oxidative stress

Inferred from genetic interaction Ref.11. Source: MGI

   Cellular_componentmitochondrial inner membrane

Inferred from electronic annotation. Source: Ensembl

mitochondrial matrix

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrial permeability transition pore complex

Traceable author statement PubMed 18309324. Source: UniProtKB

mitochondrion

Inferred from direct assay PubMed 14651853PubMed 18614015. Source: MGI

   Molecular_functioncyclosporin A binding

Inferred from electronic annotation. Source: Ensembl

peptidyl-prolyl cis-trans isomerase activity

Traceable author statement PubMed 18309324. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.11. Source: IntAct

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Tp53P023402EBI-6455001,EBI-474016

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 2929Mitochondrion By similarity
Chain30 – 206177Peptidyl-prolyl cis-trans isomerase F, mitochondrial
PRO_0000025490

Regions

Domain48 – 204157PPIase cyclophilin-type

Amino acid modifications

Modified residue661N6-acetyllysine; alternate Ref.13
Modified residue661N6-succinyllysine; alternate Ref.12
Modified residue851N6-succinyllysine Ref.12
Modified residue1661N6-acetyllysine Ref.7
Modified residue1741N6-succinyllysine Ref.12
Modified residue1891N6-succinyllysine Ref.12
Modified residue2021S-nitrosocysteine Ref.10

Sequences

Sequence LengthMass (Da)Tools
Q99KR7 [UniParc].

Last modified June 1, 2001. Version 1.
Checksum: 6E6BFE4D6B064D6F

FASTA20621,737
        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 

« Hide

References

« Hide '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.
[12]"SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-66; LYS-85; LYS-174 AND LYS-189, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
[13]"Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways."
Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B., Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.
Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
BC004041 mRNA. Translation: AAH04041.1.
CCDSCCDS26874.1.
RefSeqNP_598845.1. NM_134084.1.
XP_006518453.1. XM_006518390.1.
UniGeneMm.41656.

3D structure databases

ProteinModelPortalQ99KR7.
SMRQ99KR7. Positions 43-206.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ99KR7. 7 interactions.
MINTMINT-1856076.
STRING10090.ENSMUSP00000022419.

PTM databases

PhosphoSiteQ99KR7.

Proteomic databases

MaxQBQ99KR7.
PaxDbQ99KR7.
PRIDEQ99KR7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000022419; ENSMUSP00000022419; ENSMUSG00000021868.
GeneID105675.
KEGGmmu:105675.
UCSCuc007srr.1. mouse.

Organism-specific databases

CTD10105.
MGIMGI:2145814. Ppif.

Phylogenomic databases

eggNOGCOG0652.
GeneTreeENSGT00750000117619.
HOGENOMHOG000065981.
HOVERGENHBG001065.
InParanoidQ99KR7.
KOK09565.
OMAAFMCQAG.
OrthoDBEOG79GT7W.
PhylomeDBQ99KR7.
TreeFamTF312801.

Gene expression databases

BgeeQ99KR7.
CleanExMM_PPIF.
GenevestigatorQ99KR7.

Family and domain databases

Gene3D2.40.100.10. 1 hit.
InterProIPR029000. Cyclophilin-like_dom.
IPR024936. Cyclophilin-type_PPIase.
IPR020892. Cyclophilin-type_PPIase_CS.
IPR002130. Cyclophilin-type_PPIase_dom.
[Graphical view]
PfamPF00160. Pro_isomerase. 1 hit.
[Graphical view]
PIRSFPIRSF001467. Peptidylpro_ismrse. 1 hit.
PRINTSPR00153. CSAPPISMRASE.
SUPFAMSSF50891. SSF50891. 1 hit.
PROSITEPS00170. CSA_PPIASE_1. 1 hit.
PS50072. CSA_PPIASE_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio357826.
PROQ99KR7.
SOURCESearch...

Entry information

Entry namePPIF_MOUSE
AccessionPrimary (citable) accession number: Q99KR7
Entry history
Integrated into UniProtKB/Swiss-Prot: February 11, 2002
Last sequence update: June 1, 2001
Last modified: July 9, 2014
This is version 96 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot