PPIF_MOUSE
ID PPIF_MOUSE Reviewed; 206 AA.
AC Q99KR7;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Peptidyl-prolyl cis-trans isomerase F, mitochondrial;
DE Short=PPIase F;
DE EC=5.2.1.8 {ECO:0000250|UniProtKB:P30405};
DE AltName: Full=Cyclophilin D;
DE Short=CyP-D;
DE Short=CypD;
DE AltName: Full=Cyclophilin F;
DE AltName: Full=Rotamase F;
DE Flags: Precursor;
GN Name=Ppif;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15800626; DOI=10.1038/nature03317;
RA Nakagawa T., Shimizu S., Watanabe T., Yamaguchi O., Otsu K., Yamagata H.,
RA Inohara H., Kubo T., Tsujimoto Y.;
RT "Cyclophilin D-dependent mitochondrial permeability transition regulates
RT some necrotic but not apoptotic cell death.";
RL Nature 434:652-658(2005).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15800627; DOI=10.1038/nature03434;
RA Baines C.P., Kaiser R.A., Purcell N.H., Blair N.S., Osinska H.,
RA Hambleton M.A., Brunskill E.W., Sayen M.R., Gottlieb R.A., Dorn G.W.,
RA Robbins J., Molkentin J.D.;
RT "Loss of cyclophilin D reveals a critical role for mitochondrial
RT permeability transition in cell death.";
RL Nature 434:658-662(2005).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=16103352; DOI=10.1073/pnas.0505294102;
RA Schinzel A.C., Takeuchi O., Huang Z., Fisher J.K., Zhou Z., Rubens J.,
RA Hetz C., Danial N.N., Moskowitz M.A., Korsmeyer S.J.;
RT "Cyclophilin D is a component of mitochondrial permeability transition and
RT mediates neuronal cell death after focal cerebral ischemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:12005-12010(2005).
RN [5]
RP FUNCTION.
RX PubMed=18684715; DOI=10.1074/jbc.c800132200;
RA Basso E., Petronilli V., Forte M.A., Bernardi P.;
RT "Phosphate is essential for inhibition of the mitochondrial permeability
RT transition pore by cyclosporin A and by cyclophilin D ablation.";
RL J. Biol. Chem. 283:26307-26311(2008).
RN [6]
RP FUNCTION.
RX PubMed=19801635; DOI=10.1074/jbc.m109.020115;
RA Giorgio V., Bisetto E., Soriano M.E., Dabbeni-Sala F., Basso E.,
RA Petronilli V., Forte M.A., Bernardi P., Lippe G.;
RT "Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting
RT with the lateral stalk of the complex.";
RL J. Biol. Chem. 284:33982-33988(2009).
RN [7]
RP ACETYLATION AT LYS-166, AND INTERACTION WITH SIRT3.
RX PubMed=21212461; DOI=10.18632/aging.100252;
RA Hafner A.V., Dai J., Gomes A.P., Xiao C.Y., Palmeira C.M., Rosenzweig A.,
RA Sinclair D.A.;
RT "Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine
RT 166 suppresses age-related cardiac hypertrophy.";
RL Aging (Albany NY) 2:914-923(2010).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [9]
RP INTERACTION WITH C1QBP.
RX PubMed=20950273; DOI=10.1042/bj20101431;
RA McGee A.M., Baines C.P.;
RT "Complement 1q-binding protein inhibits the mitochondrial permeability
RT transition pore and protects against oxidative stress-induced death.";
RL Biochem. J. 433:119-125(2011).
RN [10]
RP FUNCTION, AND INTERACTION WITH ATP5F1B.
RX PubMed=21281446; DOI=10.1111/j.1742-4658.2011.08026.x;
RA Chinopoulos C., Konrad C., Kiss G., Metelkin E., Torocsik B., Zhang S.F.,
RA Starkov A.A.;
RT "Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix
RT adenine nucleotide levels.";
RL FEBS J. 278:1112-1125(2011).
RN [11]
RP S-NITROSYLATION AT CYS-202.
RX PubMed=21930693; DOI=10.1074/jbc.m111.243469;
RA Nguyen T.T., Stevens M.V., Kohr M., Steenbergen C., Sack M.N., Murphy E.;
RT "Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of
RT the mitochondrial permeability transition pore.";
RL J. Biol. Chem. 286:40184-40192(2011).
RN [12]
RP FUNCTION, AND INTERACTION WITH TP53.
RX PubMed=22726440; DOI=10.1016/j.cell.2012.05.014;
RA Vaseva A.V., Marchenko N.D., Ji K., Tsirka S.E., Holzmann S., Moll U.M.;
RT "p53 opens the mitochondrial permeability transition pore to trigger
RT necrosis.";
RL Cell 149:1536-1548(2012).
RN [13]
RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-66; LYS-85; LYS-174 AND
RP LYS-189, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=23576753; DOI=10.1073/pnas.1302961110;
RA Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B.,
RA Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.;
RT "Label-free quantitative proteomics of the lysine acetylome in mitochondria
RT identifies substrates of SIRT3 in metabolic pathways.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013).
RN [15]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=31489369; DOI=10.1126/sciadv.aaw4597;
RA Karch J., Bround M.J., Khalil H., Sargent M.A., Latchman N., Terada N.,
RA Peixoto P.M., Molkentin J.D.;
RT "Inhibition of mitochondrial permeability transition by deletion of the ANT
RT family and CypD.";
RL Sci. Adv. 5:eaaw4597-eaaw4597(2019).
CC -!- FUNCTION: PPIase that catalyzes the cis-trans isomerization of proline
CC imidic peptide bonds in oligopeptides and may therefore assist protein
CC folding (By similarity). Involved in regulation of the mitochondrial
CC permeability transition pore (mPTP) (PubMed:15800626, PubMed:15800627,
CC PubMed:16103352, PubMed:18684715, PubMed:31489369). It is proposed that
CC its association with the mPTP is masking a binding site for inhibiting
CC inorganic phosphate (Pi) and promotes the open probability of the mPTP
CC leading to apoptosis or necrosis; the requirement of the PPIase
CC activity for this function is debated (PubMed:15800626,
CC PubMed:15800627, PubMed:16103352, PubMed:18684715, PubMed:31489369). In
CC cooperation with mitochondrial p53/TP53 is involved in activating
CC oxidative stress-induced necrosis (PubMed:22726440). Involved in
CC modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and
CC regulation of mitochondrial matrix adenine nucleotide levels
CC (PubMed:19801635, PubMed:21281446). Has anti-apoptotic activity
CC independently of mPTP and in cooperation with BCL2 inhibits cytochrome
CC c-dependent apoptosis (By similarity). {ECO:0000250|UniProtKB:P29117,
CC ECO:0000250|UniProtKB:P30405, ECO:0000269|PubMed:15800626,
CC ECO:0000269|PubMed:15800627, ECO:0000269|PubMed:16103352,
CC ECO:0000269|PubMed:18684715, ECO:0000269|PubMed:19801635,
CC ECO:0000269|PubMed:21281446, ECO:0000269|PubMed:22726440,
CC ECO:0000269|PubMed:31489369}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-peptidylproline (omega=180) = [protein]-
CC peptidylproline (omega=0); Xref=Rhea:RHEA:16237, Rhea:RHEA-
CC COMP:10747, Rhea:RHEA-COMP:10748, ChEBI:CHEBI:83833,
CC ChEBI:CHEBI:83834; EC=5.2.1.8;
CC Evidence={ECO:0000250|UniProtKB:P30405};
CC -!- ACTIVITY REGULATION: Binds cyclosporin A (CsA). Is displaced by CsA
CC from the mPTP leading to a lower open probability of the mPTP.
CC {ECO:0000250|UniProtKB:P30405}.
CC -!- SUBUNIT: Associates with the mitochondrial membrane ATP synthase
CC F(1)F(0) ATP synthase; the association is increased by inorganic
CC phosphate (Pi) and decreased by cyclosporin A (CsA) (PubMed:19801635).
CC Interacts with ATP5F1B; ATP5PD and ATP5PO (PubMed:21281446). Interacts
CC with SLC25A3; the interaction is impaired by CsA (By similarity).
CC Interacts with BCL2; the interaction is impaired by CsA. Interacts with
CC TP53; the association implicates preferentially tetrameric TP53, is
CC induced by oxidative stress and is impaired by CsA (PubMed:22726440).
CC Interacts with C1QBP (PubMed:20950273). Interacts with MCUR1 (By
CC similarity). Component of the mitochondrial permeability transition
CC pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF (By
CC similarity). Interacts with SPG7 (By similarity).
CC {ECO:0000250|UniProtKB:P29117, ECO:0000250|UniProtKB:P30405,
CC ECO:0000269|PubMed:19801635, ECO:0000269|PubMed:20950273,
CC ECO:0000269|PubMed:21281446, ECO:0000269|PubMed:22726440}.
CC -!- INTERACTION:
CC Q99KR7; P02340: Tp53; NbExp=2; IntAct=EBI-6455001, EBI-474016;
CC Q99KR7; P01023: A2M; Xeno; NbExp=3; IntAct=EBI-6455001, EBI-640741;
CC Q99KR7; P50570-2: DNM2; Xeno; NbExp=3; IntAct=EBI-6455001, EBI-10968534;
CC Q99KR7; P42858: HTT; Xeno; NbExp=3; IntAct=EBI-6455001, EBI-466029;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000250|UniProtKB:P29117}.
CC -!- PTM: Acetylated at Lys-166; deacetylated at Lys-166 by SIRT3.
CC {ECO:0000269|PubMed:21212461}.
CC -!- DISRUPTION PHENOTYPE: Mice are developmentally normal and show no
CC apparent anomalies (PubMed:15800626, PubMed:15800627, PubMed:16103352).
CC Mitochondria do not undergo cyclosporin A-sensitive mitochondrial
CC permeability transtition (PubMed:15800626, PubMed:15800627,
CC PubMed:16103352). Cells show resistance to necrotic cell death induced
CC by reactive oxygen species and Ca(2+) overload, and animals show a high
CC level of resistance to ischaemia/reperfusion-induced cardiac injury
CC (PubMed:15800626, PubMed:15800627, PubMed:16103352). Mice show a
CC dramatic reduction in brain infarct size after acute middle cerebral
CC artery occlusion and reperfusion (PubMed:15800626, PubMed:15800627,
CC PubMed:16103352). Mice lacking Slc25a4/Ant1, Slc25a5/Ant2,
CC Slc25a31/Ant4 and Ppif lack Ca(2+)-induced mitochondrial permeability
CC transition pore (mPTP) formation (PubMed:31489369).
CC {ECO:0000269|PubMed:15800626, ECO:0000269|PubMed:15800627,
CC ECO:0000269|PubMed:16103352, ECO:0000269|PubMed:31489369}.
CC -!- SIMILARITY: Belongs to the cyclophilin-type PPIase family.
CC {ECO:0000305}.
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DR EMBL; BC004041; AAH04041.1; -; mRNA.
DR CCDS; CCDS26874.1; -.
DR RefSeq; NP_598845.1; NM_134084.1.
DR AlphaFoldDB; Q99KR7; -.
DR BMRB; Q99KR7; -.
DR SMR; Q99KR7; -.
DR BioGRID; 222896; 18.
DR IntAct; Q99KR7; 9.
DR MINT; Q99KR7; -.
DR STRING; 10090.ENSMUSP00000022419; -.
DR ChEMBL; CHEMBL3804752; -.
DR iPTMnet; Q99KR7; -.
DR PhosphoSitePlus; Q99KR7; -.
DR SwissPalm; Q99KR7; -.
DR EPD; Q99KR7; -.
DR jPOST; Q99KR7; -.
DR MaxQB; Q99KR7; -.
DR PaxDb; Q99KR7; -.
DR PeptideAtlas; Q99KR7; -.
DR PRIDE; Q99KR7; -.
DR ProteomicsDB; 291833; -.
DR Antibodypedia; 29865; 439 antibodies from 34 providers.
DR DNASU; 105675; -.
DR Ensembl; ENSMUST00000022419; ENSMUSP00000022419; ENSMUSG00000021868.
DR GeneID; 105675; -.
DR KEGG; mmu:105675; -.
DR UCSC; uc007srr.1; mouse.
DR CTD; 10105; -.
DR MGI; MGI:2145814; Ppif.
DR VEuPathDB; HostDB:ENSMUSG00000021868; -.
DR eggNOG; KOG0865; Eukaryota.
DR GeneTree; ENSGT00940000156008; -.
DR HOGENOM; CLU_012062_4_3_1; -.
DR InParanoid; Q99KR7; -.
DR OMA; CKGTVVN; -.
DR OrthoDB; 1403619at2759; -.
DR PhylomeDB; Q99KR7; -.
DR TreeFam; TF312801; -.
DR BioGRID-ORCS; 105675; 3 hits in 73 CRISPR screens.
DR PRO; PR:Q99KR7; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q99KR7; protein.
DR Bgee; ENSMUSG00000021868; Expressed in pyloric antrum and 254 other tissues.
DR Genevisible; Q99KR7; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005743; C:mitochondrial inner membrane; ISO:MGI.
DR GO; GO:0005759; C:mitochondrial matrix; ISO:MGI.
DR GO; GO:0005757; C:mitochondrial permeability transition pore complex; IMP:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0016018; F:cyclosporin A binding; ISS:UniProtKB.
DR GO; GO:0042277; F:peptide binding; ISO:MGI.
DR GO; GO:0003755; F:peptidyl-prolyl cis-trans isomerase activity; ISS:UniProtKB.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; IGI:MGI.
DR GO; GO:0071243; P:cellular response to arsenic-containing substance; IMP:UniProtKB.
DR GO; GO:0071277; P:cellular response to calcium ion; IMP:UniProtKB.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IMP:UniProtKB.
DR GO; GO:1902686; P:mitochondrial outer membrane permeabilization involved in programmed cell death; ISS:UniProtKB.
DR GO; GO:0070266; P:necroptotic process; IGI:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0032780; P:negative regulation of ATP-dependent activity; IMP:UniProtKB.
DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0090324; P:negative regulation of oxidative phosphorylation; IMP:UniProtKB.
DR GO; GO:2000276; P:negative regulation of oxidative phosphorylation uncoupler activity; IMP:UniProtKB.
DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; ISS:UniProtKB.
DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IMP:UniProtKB.
DR GO; GO:0006457; P:protein folding; IBA:GO_Central.
DR GO; GO:0000413; P:protein peptidyl-prolyl isomerization; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; ISO:MGI.
DR GO; GO:0046902; P:regulation of mitochondrial membrane permeability; IMP:UniProtKB.
DR GO; GO:1902445; P:regulation of mitochondrial membrane permeability involved in programmed necrotic cell death; IMP:UniProtKB.
DR GO; GO:0010939; P:regulation of necrotic cell death; IDA:UniProtKB.
DR GO; GO:0010849; P:regulation of proton-transporting ATPase activity, rotational mechanism; IMP:UniProtKB.
DR GO; GO:0002931; P:response to ischemia; IMP:UniProtKB.
DR GO; GO:0006979; P:response to oxidative stress; IGI:MGI.
DR Gene3D; 2.40.100.10; -; 1.
DR InterPro; IPR029000; Cyclophilin-like_dom_sf.
DR InterPro; IPR020892; Cyclophilin-type_PPIase_CS.
DR InterPro; IPR002130; Cyclophilin-type_PPIase_dom.
DR Pfam; PF00160; Pro_isomerase; 1.
DR PRINTS; PR00153; CSAPPISMRASE.
DR SUPFAM; SSF50891; SSF50891; 1.
DR PROSITE; PS00170; CSA_PPIASE_1; 1.
DR PROSITE; PS50072; CSA_PPIASE_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Apoptosis; Isomerase; Mitochondrion; Necrosis;
KW Reference proteome; Rotamase; S-nitrosylation; Transit peptide.
FT TRANSIT 1..29
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 30..206
FT /note="Peptidyl-prolyl cis-trans isomerase F,
FT mitochondrial"
FT /id="PRO_0000025490"
FT DOMAIN 48..204
FT /note="PPIase cyclophilin-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00156"
FT MOD_RES 66
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23576753"
FT MOD_RES 66
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 85
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 166
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:21212461"
FT MOD_RES 174
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 189
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 202
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000269|PubMed:21930693"
SQ SEQUENCE 206 AA; 21737 MW; 6E6BFE4D6B064D6F CRC64;
MLALRCGPRL LGLLSGPRSA PLLLSATRTC SDGGARGANS SSGNPLVYLD VGADGQPLGR
VVLELKADVV PKTAENFRAL CTGEKGFGYK GSTFHRVIPA FMCQAGDFTN HNGTGGRSIY
GSRFPDENFT LKHVGPGVLS MANAGPNTNG SQFFICTIKT DWLDGKHVVF GHVKEGMDVV
KKIESFGSKS GKTSKKIVIT DCGQLS
