ID PPM1K_MOUSE Reviewed; 372 AA. AC Q8BXN7; DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 27-MAR-2024, entry version 148. DE RecName: Full=Protein phosphatase Mn(2+)-dependent 1K; DE AltName: Full=Branched-chain alpha-ketoacid dehydrogenase phosphatase {ECO:0000250|UniProtKB:Q8N3J5}; DE Short=BCKDH {ECO:0000250|UniProtKB:Q8N3J5}; DE Short=BDP {ECO:0000250|UniProtKB:Q8N3J5}; DE EC=3.1.3.16 {ECO:0000250|UniProtKB:Q8N3J5}; DE AltName: Full=Protein phosphatase 2C family member {ECO:0000250|UniProtKB:Q8N3J5}; DE AltName: Full=Protein phosphatase 2C isoform kappa; DE Short=PP2C-kappa; DE AltName: Full=[3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphatase; DE EC=3.1.3.52 {ECO:0000250|UniProtKB:Q8N3J5}; DE Flags: Precursor; GN Name=Ppm1k {ECO:0000303|PubMed:22589535, ECO:0000312|MGI:MGI:2442111}; GN Synonyms=Pp2cm {ECO:0000303|PubMed:22589535}; 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 [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=17374715; DOI=10.1101/gad.1499107; RA Lu G., Ren S., Korge P., Choi J., Dong Y., Weiss J., Koehler C., RA Chen J.-N., Wang Y.; RT "A novel mitochondrial matrix serine/threonine protein phosphatase RT regulates the mitochondria permeability transition pore and is essential RT for cellular survival and development."; RL Genes Dev. 21:784-796(2007). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Retina; 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Head; 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 [4] RP TISSUE SPECIFICITY. RX PubMed=17336929; DOI=10.1016/j.bbrc.2007.02.108; RA Joshi M.A., Jeoung N.H., Popov K.M., Harris R.A.; RT "Identification of a novel PP2C-type mitochondrial phosphatase."; RL Biochem. Biophys. Res. Commun. 356:38-44(2007). RN [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [6] RP FUNCTION, CATALYTIC ACTIVITY, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=19411760; DOI=10.1172/jci38151; RA Lu G., Sun H., She P., Youn J.Y., Warburton S., Ping P., Vondriska T.M., RA Cai H., Lynch C.J., Wang Y.; RT "Protein phosphatase 2Cm is a critical regulator of branched-chain amino RT acid catabolism in mice and cultured cells."; RL J. Clin. Invest. 119:1678-1687(2009). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-248, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, RC Pancreas, 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 [8] RP TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND INDUCTION. RX PubMed=22589535; DOI=10.1074/jbc.m112.351031; RA Zhou M., Lu G., Gao C., Wang Y., Sun H.; RT "Tissue-specific and nutrient regulation of the branched-chain alpha-keto RT acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm)."; RL J. Biol. Chem. 287:23397-23406(2012). CC -!- FUNCTION: Serine/threonine-protein phosphatase component of CC macronutrients metabolism. Forms a functional kinase and phosphatase CC pair with BCKDK, serving as a metabolic regulatory node that CC coordinates branched-chain amino acids (BCAAs) with glucose and lipid CC metabolism via two distinct phosphoprotein targets: mitochondrial CC BCKDHA subunit of the branched-chain alpha-ketoacid dehydrogenase CC (BCKDH) complex and cytosolic ACLY, a lipogenic enzyme of Krebs cycle CC (By similarity). At high levels of branched-chain ketoacids, CC dephosphorylates and activates mitochondrial BCKDH complex, a CC multisubunit complex consisting of three multimeric components each CC involved in different steps of BCAA catabolism: E1 composed of BCKDHA CC and BCKDHB, E2 core composed of DBT monomers, and E3 composed of DLD CC monomers. Tightly associates with the E2 component of BCKDH complex and CC dephosphorylates BCKDHA on Ser-334 (By similarity). Regulates the CC reversible phosphorylation of ACLY in response to changes in cellular CC carbohydrate abundance such as occurs during fasting to feeding CC metabolic transition. At fasting state, appears to dephosphorylate ACLY CC on Ser-455 and inactivate it. Refeeding stimulates MLXIPL/ChREBP CC transcription factor, leading to increased BCKDK to PPM1K expression CC ratio, phosphorylation and activation of ACLY that ultimately results CC in the generation of malonyl-CoA and oxaloacetate immediate substrates CC of de novo lipogenesis and gluconeogenesis, respectively (By CC similarity). Recognizes phosphosites having SxS or RxxS motifs and CC strictly depends on Mn(2+) ions for the phosphatase activity (By CC similarity). Regulates Ca(2+)-induced opening of mitochondrial CC transition pore and apoptotic cell death (PubMed:17374715, CC PubMed:19411760) (By similarity). {ECO:0000250|UniProtKB:Q8N3J5, CC ECO:0000269|PubMed:17374715, ECO:0000269|PubMed:19411760}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + O-phospho-L-seryl-[3-methyl-2-oxobutanoate CC dehydrogenase] = L-seryl-[3-methyl-2-oxobutanoate dehydrogenase] + CC phosphate; Xref=Rhea:RHEA:77247, Rhea:RHEA-COMP:13695, Rhea:RHEA- CC COMP:13696, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:83421; EC=3.1.3.52; CC Evidence={ECO:0000250|UniProtKB:Q8N3J5}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77248; CC Evidence={ECO:0000250|UniProtKB:Q8N3J5}; 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:0000269|PubMed:19411760}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20630; CC Evidence={ECO:0000269|PubMed:19411760}; CC -!- COFACTOR: CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000250|UniProtKB:Q8N3J5}; CC Note=Binds 2 Mn(2+) ions per subunit. {ECO:0000250|UniProtKB:Q8N3J5}; CC -!- PATHWAY: Protein modification. {ECO:0000250|UniProtKB:Q8N3J5}. CC -!- SUBUNIT: Monomer. Interacts with E1 and E2 components of the branched- CC chain alpha-ketoacid dehydrogenase (BCKDH) complex; this interaction CC requires colocalization in mitochondria. Interacts with BCKDHA but not CC with BCKDHB of the E1 component. Interacts with the 24-meric E2 core CC composed of DBT monomers with a 24:1 stoichiometry; the N-terminal CC region (residues 49-61) of PPM1K and C-terminal linker of the lipoyl CC domain of DBT (residues 145-160) are critical for this interaction, CC whereas the lipoyl prosthetic group is dispensable. Competes with BCKDK CC for binding to the E2 core; this interaction is modulated by branched- CC chain alpha-keto acids. At steady state, BCKDH holoenzyme CC preferentially binds BCKDK and BCKDHA is phosphorylated. In response to CC high levels of branched-chain alpha-keto acids, the inhibitory BCKDK is CC replaced by activating PPM1K leading to BCKDHA dephosphorylation and CC BCAA degradation. {ECO:0000250|UniProtKB:Q8N3J5}. CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix CC {ECO:0000250|UniProtKB:Q8N3J5}. Note=Detected in the cytosolic CC compartment of liver cells. {ECO:0000250|UniProtKB:A6K136}. CC -!- TISSUE SPECIFICITY: Highly expressed in the heart, kidney, brain and CC liver and to a lesser extent in testis, lung, spleen and adipose CC tissue. Very low amount in muscle (at protein level). Also expressed in CC the thymus (at protein level) and the diaphragm. Significantly reduced CC in hypertrophied hearts. {ECO:0000269|PubMed:17336929, CC ECO:0000269|PubMed:17374715, ECO:0000269|PubMed:19411760, CC ECO:0000269|PubMed:22589535}. CC -!- DEVELOPMENTAL STAGE: In the developing embryos detected in heart and CC brain structures as early as 10.5 dpc and in liver at 14.5 dpc. CC {ECO:0000269|PubMed:22589535}. CC -!- INDUCTION: Transcriptionally regulated by nutrient level of BCAAs. CC {ECO:0000269|PubMed:22589535}. CC -!- DISRUPTION PHENOTYPE: Mice are born at the expected Mendelian ratio and CC display no developmental abnormalities if fed normal diet. However CC high-protein diet, either during pregnancy or during the postnatal CC period, results in increased plasma BCAA levels and premature mortality CC in neonates. {ECO:0000269|PubMed:19411760}. CC -!- SIMILARITY: Belongs to the PP2C family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK044610; BAC32001.1; -; mRNA. DR EMBL; BC092238; AAH92238.1; -; mRNA. DR CCDS; CCDS20183.1; -. DR RefSeq; NP_780732.1; NM_175523.4. DR AlphaFoldDB; Q8BXN7; -. DR SMR; Q8BXN7; -. DR STRING; 10090.ENSMUSP00000041395; -. DR iPTMnet; Q8BXN7; -. DR PhosphoSitePlus; Q8BXN7; -. DR MaxQB; Q8BXN7; -. DR PaxDb; 10090-ENSMUSP00000041395; -. DR ProteomicsDB; 291715; -. DR Antibodypedia; 14616; 184 antibodies from 28 providers. DR DNASU; 243382; -. DR Ensembl; ENSMUST00000042766.6; ENSMUSP00000041395.4; ENSMUSG00000037826.6. DR GeneID; 243382; -. DR KEGG; mmu:243382; -. DR UCSC; uc009cch.1; mouse. DR AGR; MGI:2442111; -. DR CTD; 152926; -. DR MGI; MGI:2442111; Ppm1k. DR VEuPathDB; HostDB:ENSMUSG00000037826; -. DR eggNOG; KOG0698; Eukaryota. DR GeneTree; ENSGT00940000156633; -. DR HOGENOM; CLU_013173_1_3_1; -. DR InParanoid; Q8BXN7; -. DR OMA; CHTHMKK; -. DR OrthoDB; 202023at2759; -. DR PhylomeDB; Q8BXN7; -. DR TreeFam; TF354344; -. DR Reactome; R-MMU-70895; Branched-chain amino acid catabolism. DR BioGRID-ORCS; 243382; 2 hits in 76 CRISPR screens. DR ChiTaRS; Ppm1k; mouse. DR PRO; PR:Q8BXN7; -. DR Proteomes; UP000000589; Chromosome 6. DR RNAct; Q8BXN7; Protein. DR Bgee; ENSMUSG00000037826; Expressed in retrosplenial region and 219 other cell types or tissues. DR ExpressionAtlas; Q8BXN7; baseline and differential. DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; HDA:MGI. DR GO; GO:0030145; F:manganese ion binding; ISO:MGI. DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC. DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; ISO:MGI. DR GO; GO:0009083; P:branched-chain amino acid catabolic process; IEA:Ensembl. DR GO; GO:1902108; P:regulation of mitochondrial membrane permeability involved in apoptotic process; IMP:UniProtKB. DR CDD; cd00143; PP2Cc; 1. DR Gene3D; 3.60.40.10; PPM-type phosphatase domain; 1. DR InterPro; IPR015655; PP2C. DR InterPro; IPR000222; PP2C_BS. DR InterPro; IPR036457; PPM-type-like_dom_sf. DR InterPro; IPR001932; PPM-type_phosphatase-like_dom. DR PANTHER; PTHR47992; PROTEIN PHOSPHATASE; 1. DR PANTHER; PTHR47992:SF226; PROTEIN PHOSPHATASE 1K, MITOCHONDRIAL; 1. DR Pfam; PF00481; PP2C; 1. DR SMART; SM00331; PP2C_SIG; 1. DR SMART; SM00332; PP2Cc; 1. DR SUPFAM; SSF81606; PP2C-like; 1. DR PROSITE; PS01032; PPM_1; 1. DR PROSITE; PS51746; PPM_2; 1. DR Genevisible; Q8BXN7; MM. PE 1: Evidence at protein level; KW Hydrolase; Manganese; Metal-binding; Mitochondrion; Phosphoprotein; KW Protein phosphatase; Reference proteome; Transit peptide. FT TRANSIT 1..29 FT /note="Mitochondrion" FT CHAIN 30..372 FT /note="Protein phosphatase Mn(2+)-dependent 1K" FT /id="PRO_0000278209" FT DOMAIN 94..346 FT /note="PPM-type phosphatase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01082" FT REGION 46..61 FT /note="Critical for association with the BCKDH complex" FT /evidence="ECO:0000250|UniProtKB:Q8N3J5" FT BINDING 127 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q8N3J5" FT BINDING 127 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q8N3J5" FT BINDING 128 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q8N3J5" FT BINDING 298 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q8N3J5" FT BINDING 337 FT /ligand="Mn(2+)" FT /ligand_id="ChEBI:CHEBI:29035" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q8N3J5" FT MOD_RES 248 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17242355, FT ECO:0007744|PubMed:21183079" SQ SEQUENCE 372 AA; 40918 MW; 3749BEB94F211E7A CRC64; MLSAAFITLL RSGGNQVKKR VLLSSILLQD HRQATPACYF STSEARCSRF DPDGSGQPAT WDNFGIWDNR IDEPILLPPS IKYGKPIPKI SLENVGCASL IGKRKENEDR FGFAQLTEEV LYFAVYDGHG GPAAADFCHT HMEKCVMDLL PREKDLETVL TLAFLEIDKA FASYAHLSAD ASLLTSGTTA TVALLRDGVE LVVASVGDSR ALLCRKGKPM KLTTDHTPER KDEKERIKKF GGFVAWNSLG QPHVNGRLAM TRSIGDLDLK ASGVIAEPET TRIKLYHADD SFLVLTTDGI NFMVNSQEIC DFVNQCHDPK EAAHSVTEQA IQYGTEDNST AVVVPFGAWG KYKNSEITFS FSRSFASSGR WA //