ID PGAM5_MOUSE Reviewed; 288 AA.
AC Q8BX10; B2RSM6; Q3UK19; Q80VY8; Q8BM78; Q9CZU2;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 27-MAR-2024, entry version 146.
DE RecName: Full=Serine/threonine-protein phosphatase PGAM5, mitochondrial;
DE EC=3.1.3.16;
DE AltName: Full=Phosphoglycerate mutase family member 5;
GN Name=Pgam5;
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] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J, DBA/2J, and NOD; TISSUE=Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 7-288 (ISOFORM 1).
RC TISSUE=Brain, and Embryo;
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 [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Heart, Kidney, Liver, 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 [4]
RP FUNCTION.
RX PubMed=22265414; DOI=10.1016/j.cell.2011.11.030;
RA Wang Z., Jiang H., Chen S., Du F., Wang X.;
RT "The mitochondrial phosphatase PGAM5 functions at the convergence point of
RT multiple necrotic death pathways.";
RL Cell 148:228-243(2012).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=32439975; DOI=10.1038/s41467-020-16312-7;
RA Yu B., Ma J., Li J., Wang D., Wang Z., Wang S.;
RT "Mitochondrial phosphatase PGAM5 modulates cellular senescence by
RT regulating mitochondrial dynamics.";
RL Nat. Commun. 11:2549-2549(2020).
CC -!- FUNCTION: Mitochondrial serine/threonine phosphatase that
CC dephosphorylates various substrates and thus plays a role in different
CC biological processes including cellular senescence or mitophagy.
CC Modulates cellular senescence by regulating mitochondrial dynamics.
CC Mechanistically, participates in mitochondrial fission through
CC dephosphorylating DNM1L/DRP1. Additionally, dephosphorylates MFN2 in a
CC stress-sensitive manner and consequently protects it from
CC ubiquitination and degradation to promote mitochondrial network
CC formation. Regulates mitophagy independent of PARKIN by interacting
CC with and dephosphorylating FUNDC1, which interacts with LC3. Regulates
CC anti-oxidative response by forming a tertiary complex with KEAP1 and
CC NRF2 (By similarity). Regulates necroptosis by acting as a RIPK3 target
CC and recruiting the RIPK1-RIPK3-MLKL necrosis 'attack' complex to
CC mitochondria (PubMed:22265414). {ECO:0000250|UniProtKB:Q96HS1,
CC ECO:0000269|PubMed:22265414}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] +
CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:83421; EC=3.1.3.16;
CC Evidence={ECO:0000250|UniProtKB:Q96HS1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:61977; EC=3.1.3.16;
CC Evidence={ECO:0000250|UniProtKB:Q96HS1};
CC -!- SUBUNIT: Dimer. Forms a ternary complex with NFE2L2 and KEAP1.
CC Interacts with BCL2L1 and MAP3K5. Upon TNF-induced necrosis, forms in
CC complex with RIPK1, RIPK3 and MLKL; the formation of this complex leads
CC to PGAM5 phosphorylation. Isoform 2, but not isoform 1, interacts with
CC DNM1L; this interaction leads to DNM1L dephosphorylation and activation
CC and eventually to mitochondria fragmentation.
CC {ECO:0000250|UniProtKB:Q96HS1}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane
CC {ECO:0000250|UniProtKB:Q96HS1}; Single-pass membrane protein
CC {ECO:0000255}. Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:Q96HS1}; Single-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8BX10-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BX10-2; Sequence=VSP_025762;
CC -!- DOMAIN: The N-terminal 35 amino acids, including the potential
CC transmembrane alpha-helix, function as a non-cleaved mitochondrial
CC targeting sequence that targets the protein to the cytosolic side of
CC the outer mitochondrial membrane. {ECO:0000250}.
CC -!- PTM: Phosphorylated by the RIPK1/RIPK3 complex under necrotic
CC conditions. This phosphorylation increases PGAM5 phosphatase activity
CC (By similarity). {ECO:0000250}.
CC -!- PTM: Proteolytically cleaved by PARL in response to loss of
CC mitochondrial membrane potential. {ECO:0000250|UniProtKB:Q96HS1}.
CC -!- DISRUPTION PHENOTYPE: Deletion mutant mice were born at mendel ratio,
CC but weighed significantly less compared to the wild-type (WT) controls
CC at 1-year and older. About 50% of the mutant mice (aged 1-1.5 years)
CC showed lordokyphosis (hunchback), odd gait and swollen foot, and among
CC them about 50% died from unknown causes. These suggest an accelerated
CC senescence (or aging) phenotype in deletion mutant mice.
CC {ECO:0000269|PubMed:32439975}.
CC -!- SIMILARITY: Belongs to the phosphoglycerate mutase family. BPG-
CC dependent PGAM subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB28067.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK012159; BAB28067.1; ALT_FRAME; mRNA.
DR EMBL; AK034588; BAC28763.1; -; mRNA.
DR EMBL; AK049246; BAC33634.1; -; mRNA.
DR EMBL; AK146216; BAE26984.1; -; mRNA.
DR EMBL; AK169643; BAE41272.1; -; mRNA.
DR EMBL; BC052179; AAH52179.1; -; mRNA.
DR EMBL; BC138924; AAI38925.1; -; mRNA.
DR EMBL; BC138925; AAI38926.1; -; mRNA.
DR CCDS; CCDS19523.1; -. [Q8BX10-2]
DR CCDS; CCDS51606.1; -. [Q8BX10-1]
DR RefSeq; NP_001157010.1; NM_001163538.1. [Q8BX10-1]
DR RefSeq; NP_082549.2; NM_028273.3. [Q8BX10-2]
DR AlphaFoldDB; Q8BX10; -.
DR SMR; Q8BX10; -.
DR BioGRID; 215426; 21.
DR DIP; DIP-32064N; -.
DR IntAct; Q8BX10; 5.
DR MINT; Q8BX10; -.
DR STRING; 10090.ENSMUSP00000108124; -.
DR ChEMBL; CHEMBL2331071; -.
DR iPTMnet; Q8BX10; -.
DR PhosphoSitePlus; Q8BX10; -.
DR SwissPalm; Q8BX10; -.
DR EPD; Q8BX10; -.
DR MaxQB; Q8BX10; -.
DR PaxDb; 10090-ENSMUSP00000108124; -.
DR PeptideAtlas; Q8BX10; -.
DR ProteomicsDB; 288046; -. [Q8BX10-1]
DR ProteomicsDB; 288047; -. [Q8BX10-2]
DR Pumba; Q8BX10; -.
DR Antibodypedia; 49123; 72 antibodies from 16 providers.
DR DNASU; 72542; -.
DR Ensembl; ENSMUST00000059229.16; ENSMUSP00000057760.9; ENSMUSG00000029500.17. [Q8BX10-2]
DR Ensembl; ENSMUST00000112505.9; ENSMUSP00000108124.3; ENSMUSG00000029500.17. [Q8BX10-1]
DR GeneID; 72542; -.
DR KEGG; mmu:72542; -.
DR UCSC; uc008yqh.2; mouse. [Q8BX10-2]
DR UCSC; uc008yqi.2; mouse. [Q8BX10-1]
DR AGR; MGI:1919792; -.
DR CTD; 192111; -.
DR MGI; MGI:1919792; Pgam5.
DR VEuPathDB; HostDB:ENSMUSG00000029500; -.
DR eggNOG; KOG4609; Eukaryota.
DR GeneTree; ENSGT00390000004796; -.
DR HOGENOM; CLU_063130_0_1_1; -.
DR InParanoid; Q8BX10; -.
DR OMA; QLPLFAW; -.
DR OrthoDB; 2994603at2759; -.
DR PhylomeDB; Q8BX10; -.
DR TreeFam; TF314977; -.
DR BRENDA; 3.9.1.3; 3474.
DR Reactome; R-MMU-8934903; Receptor Mediated Mitophagy.
DR BioGRID-ORCS; 72542; 3 hits in 80 CRISPR screens.
DR ChiTaRS; Pgam5; mouse.
DR PRO; PR:Q8BX10; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q8BX10; Protein.
DR Bgee; ENSMUSG00000029500; Expressed in dorsal pancreas and 256 other cell types or tissues.
DR ExpressionAtlas; Q8BX10; baseline and differential.
DR Genevisible; Q8BX10; MM.
DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0005096; F:GTPase activator activity; ISS:UniProtKB.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0016791; F:phosphatase activity; ISS:UniProtKB.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0016311; P:dephosphorylation; ISS:UniProtKB.
DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab.
DR GO; GO:0090141; P:positive regulation of mitochondrial fission; IBA:GO_Central.
DR CDD; cd07067; HP_PGM_like; 1.
DR Gene3D; 3.40.50.1240; Phosphoglycerate mutase-like; 1.
DR InterPro; IPR013078; His_Pase_superF_clade-1.
DR InterPro; IPR029033; His_PPase_superfam.
DR PANTHER; PTHR20935; PHOSPHOGLYCERATE MUTASE-RELATED; 1.
DR PANTHER; PTHR20935:SF0; SERINE_THREONINE-PROTEIN PHOSPHATASE PGAM5, MITOCHONDRIAL; 1.
DR Pfam; PF00300; His_Phos_1; 1.
DR SMART; SM00855; PGAM; 1.
DR SUPFAM; SSF53254; Phosphoglycerate mutase-like; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Hydrolase; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Mitochondrion outer membrane; Necrosis;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..288
FT /note="Serine/threonine-protein phosphatase PGAM5,
FT mitochondrial"
FT /id="PRO_0000288783"
FT TOPO_DOM 1..6
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT TRANSMEM 7..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 30..288
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT REGION 76..81
FT /note="Interaction with KEAP1"
FT /evidence="ECO:0000250"
FT SITE 24..25
FT /note="Cleavage; by PARL"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT MOD_RES 79
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT MOD_RES 86
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT MOD_RES 115
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT MOD_RES 143
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT MOD_RES 190
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q96HS1"
FT VAR_SEQ 195
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_025762"
FT CONFLICT 46
FT /note="A -> V (in Ref. 1; BAE26984)"
FT /evidence="ECO:0000305"
FT CONFLICT 102
FT /note="I -> M (in Ref. 1; BAC28763)"
FT /evidence="ECO:0000305"
FT CONFLICT 144
FT /note="I -> V (in Ref. 1; BAB28067)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 288 AA; 31994 MW; B704CDF4E640F888 CRC64;
MAFRQALQLA ACGLAGGSAA VLFSAVAVGK PRGGGDADTR ATEPPAWTGA RAGRGVWDTN
WDRREPLSLI NLKKRNVESG EDELTSRLDH YKAKATRHIF LIRHSQYHVD GSLEKDRTLT
PLGREQAELT GLRLASLGLK FNKIVHSSMT RAVETTDIIS KHLPGVSRVS TDLLREGAPI
EPDPPVSHWK PEAVQYYEDG ARIEAAFRNY IHRADARQEE DSYEIFICHA NVIRYIVCRA
LQFPPEGWLR LSLNNGSITH LVIRPNGRVA LRTLGDTGFM PPDKITRS
//
