ID PPM1K_HUMAN Reviewed; 372 AA. AC Q8N3J5; B2RAZ1; Q05CT5; Q49AB5; Q4W5E6; Q56AN8; Q8IUZ7; Q8IXG7; AC Q8ND70; Q96NT4; DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2002, sequence version 1. DT 09-JUL-2014, entry version 101. DE RecName: Full=Protein phosphatase 1K, mitochondrial; DE EC=3.1.3.16; DE AltName: Full=PP2C domain-containing protein phosphatase 1K; DE AltName: Full=PP2C-like mitochondrial protein; DE AltName: Full=PP2C-type mitochondrial phosphoprotein phosphatase; DE Short=PTMP; DE AltName: Full=Protein phosphatase 2C isoform kappa; DE Short=PP2C-kappa; DE Flags: Precursor; GN Name=PPM1K; Synonyms=PP2CM; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR RP LOCATION, TRANSIT PEPTIDE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-298. 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 RT essential for cellular survival and development."; RL Genes Dev. 21:784-796(2007). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RA Mao Y., Xie Y., Dai J.; RT "Cloning and characterization of a novel human PP2C gene from fetal RT brain."; RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, AND RP BIOPHYSICOCHEMICAL PROPERTIES. 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 [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Xu J., Stagliano N., Deponte J. III, Rodrigue-Way A., Golden S., RA Katz S., Jeyaseelan R., Donoghue M., Meyers R., Gottfried S., RA Wysong D., McGovern K., Pollman M., Breitbart R.E., Acton S.; RT "Protein phosphatase 2C kappa is upregulated in heart failure and RT attenuates agonist-induced cardiomyocyte hypertrophy."; RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Cerebellum, and Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Amygdala, and Lymph node; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J., RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., RA Waterston R.H., Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 RT and 4."; RL Nature 434:724-731(2005). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND VARIANT RP LYS-94. RC TISSUE=Pancreas, and Testis; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [10] RP INVOLVEMENT IN MSUDMV. RX PubMed=23086801; DOI=10.1002/humu.22242; RA Oyarzabal A., Martinez-Pardo M., Merinero B., Navarrete R., RA Desviat L.R., Ugarte M., Rodriguez-Pombo P.; RT "A novel regulatory defect in the branched-chain alpha-keto acid RT dehydrogenase complex due to a mutation in the PPM1K gene causes a RT mild variant phenotype of maple syrup urine disease."; RL Hum. Mutat. 34:355-362(2013). RN [11] RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 89-351, AND RP MAGNESIUM-BINDING. RX PubMed=18058037; DOI=10.1007/s10969-007-9036-1; RA Almo S.C., Bonanno J.B., Sauder J.M., Emtage S., Dilorenzo T.P., RA Malashkevich V., Wasserman S.R., Swaminathan S., Eswaramoorthy S., RA Agarwal R., Kumaran D., Madegowda M., Ragumani S., Patskovsky Y., RA Alvarado J., Ramagopal U.A., Faber-Barata J., Chance M.R., Sali A., RA Fiser A., Zhang Z.Y., Lawrence D.S., Burley S.K.; RT "Structural genomics of protein phosphatases."; RL J. Struct. Funct. Genomics 8:121-140(2007). RN [12] RP VARIANT HIS-26. RX PubMed=23200863; DOI=10.1016/j.ajhg.2012.10.024; RA Charlesworth G., Plagnol V., Holmstroem K.M., Bras J., Sheerin U.M., RA Preza E., Rubio-Agusti I., Ryten M., Schneider S.A., Stamelou M., RA Trabzuni D., Abramov A.Y., Bhatia K.P., Wood N.W.; RT "Mutations in ANO3 cause dominant craniocervical dystonia: ion channel RT implicated in pathogenesis."; RL Am. J. Hum. Genet. 91:1041-1050(2012). CC -!- FUNCTION: Regulates the mitochondrial permeability transition pore CC and is essential for cellular survival and development. CC -!- CATALYTIC ACTIVITY: [a protein]-serine/threonine phosphate + H(2)O CC = [a protein]-serine/threonine + phosphate. CC -!- COFACTOR: Binds 1 magnesium or manganese ion per subunit. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=10.7 mM for p-nitrophenylphosphate; CC Vmax=3.6 umol/min/mg enzyme toward p-nitrophenylphosphate (at 30 CC degrees Celsius); CC Vmax=4 nmol/min/mg enzyme toward branched-chain alpha-ketoacid CC dehydrogenase complex (at 37 degrees Celsius); CC Note=Half maximal activity toward p-nitrophenylphosphate CC achieved with 3.7 mM of manganese ions; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8N3J5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8N3J5-2; Sequence=VSP_023158, VSP_023159; CC Name=3; CC IsoId=Q8N3J5-3; Sequence=VSP_023156, VSP_023157; CC -!- DISEASE: Maple syrup urine disease, mild variant (MSUDMV) CC [MIM:615135]: A mild form of maple syrup urine disease, a CC metabolic disorder due to an enzyme defect in the catabolic CC pathway of the branched-chain amino acids leucine, isoleucine, and CC valine. Accumulation of these 3 amino acids and their CC corresponding keto acids leads to encephalopathy and progressive CC neurodegeneration. Clinical features include mental and physical CC retardation, feeding problems, and a maple syrup odor to the CC urine. The keto acids of the branched-chain amino acids are CC present in the urine. If untreated, maple syrup urine disease can CC lead to seizures, coma, and death. The disease is often classified CC by its pattern of signs and symptoms. The most common and severe CC form of the disease is the classic type, which becomes apparent CC soon after birth. Variant forms of the disorder become apparent CC later in infancy or childhood and are typically milder, but they CC still involve developmental delay and other medical problems if CC not treated. MSUDMV is characterized by increased plasma levels of CC branched-chain amino acids (BCAA) apparent at birth. Treatment CC with a low-protein diet free of BCAA can result in normal CC psychomotor development and lack of metabolic episodes. Note=The CC gene represented in this entry is involved in disease CC pathogenesis. CC -!- SIMILARITY: Belongs to the PP2C family. CC -!- SIMILARITY: Contains 1 PP2C-like domain. CC -!- CAUTION: PubMed:18058037 has crystallized PPM1K in the presence of CC magnesium ions. However, PubMed:17336929 reported that no activity CC toward p-nitrophenylphosphate was seen in the absence of manganese CC ions and magnesium could not substitute for manganese. 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; AY157615; AAO17296.1; -; mRNA. DR EMBL; AF351614; AAN76514.1; -; mRNA. DR EMBL; AY994097; AAX77016.1; -; mRNA. DR EMBL; AY435431; AAR06213.1; -; mRNA. DR EMBL; AK054678; BAB70790.1; -; mRNA. DR EMBL; AK314417; BAG37038.1; -; mRNA. DR EMBL; AL834167; CAD38869.2; -; mRNA. DR EMBL; AL834271; CAD38946.1; -; mRNA. DR EMBL; AC107067; AAY41021.1; -; Genomic_DNA. DR EMBL; AC108213; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471057; EAX06016.1; -; Genomic_DNA. DR EMBL; BC020850; AAH20850.1; ALT_TERM; mRNA. DR EMBL; BC037552; AAH37552.1; -; mRNA. DR EMBL; BC041350; AAH41350.1; -; mRNA. DR CCDS; CCDS3629.1; -. [Q8N3J5-1] DR RefSeq; NP_689755.3; NM_152542.4. [Q8N3J5-1] DR RefSeq; XP_006714174.1; XM_006714111.1. [Q8N3J5-1] DR UniGene; Hs.43744; -. DR PDB; 2IQ1; X-ray; 2.25 A; A=89-351. DR PDB; 4DA1; X-ray; 2.38 A; A=84-360. DR PDBsum; 2IQ1; -. DR PDBsum; 4DA1; -. DR ProteinModelPortal; Q8N3J5; -. DR SMR; Q8N3J5; 90-349. DR BioGrid; 127472; 2. DR IntAct; Q8N3J5; 1. DR MINT; MINT-4725175; -. DR PhosphoSite; Q8N3J5; -. DR DMDM; 74750962; -. DR PaxDb; Q8N3J5; -. DR PRIDE; Q8N3J5; -. DR DNASU; 152926; -. DR Ensembl; ENST00000315194; ENSP00000324761; ENSG00000163644. [Q8N3J5-2] DR Ensembl; ENST00000608933; ENSP00000477341; ENSG00000163644. [Q8N3J5-1] DR GeneID; 152926; -. DR KEGG; hsa:152926; -. DR UCSC; uc003hrm.5; human. [Q8N3J5-1] DR UCSC; uc003hrn.4; human. [Q8N3J5-2] DR CTD; 152926; -. DR GeneCards; GC04M089178; -. DR HGNC; HGNC:25415; PPM1K. DR HPA; HPA020066; -. DR HPA; HPA020862; -. DR HPA; HPA023891; -. DR MIM; 611065; gene. DR MIM; 615135; phenotype. DR neXtProt; NX_Q8N3J5; -. DR Orphanet; 268162; Intermediate maple syrup urine disease. DR PharmGKB; PA134912083; -. DR eggNOG; COG0631; -. DR HOVERGEN; HBG096199; -. DR InParanoid; Q8N3J5; -. DR KO; K17505; -. DR OMA; IVPFGAW; -. DR OrthoDB; EOG7992QN; -. DR PhylomeDB; Q8N3J5; -. DR TreeFam; TF354344; -. DR BRENDA; 3.1.3.16; 2681. DR EvolutionaryTrace; Q8N3J5; -. DR GeneWiki; PPM1K; -. DR GenomeRNAi; 152926; -. DR NextBio; 87055; -. DR PRO; PR:Q8N3J5; -. DR Bgee; Q8N3J5; -. DR Genevestigator; Q8N3J5; -. DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IEA:InterPro. DR GO; GO:0006470; P:protein dephosphorylation; IEA:InterPro. DR Gene3D; 3.60.40.10; -; 1. DR InterPro; IPR001932; PP2C-like_dom. DR InterPro; IPR000222; PP2C_Mn2_Asp60_BS. DR InterPro; IPR015655; Protein_Pase_2C. DR PANTHER; PTHR13832; PTHR13832; 1. DR Pfam; PF00481; PP2C; 1. DR SMART; SM00331; PP2C_SIG; 1. DR SMART; SM00332; PP2Cc; 1. DR SUPFAM; SSF81606; SSF81606; 1. DR PROSITE; PS01032; PP2C; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; Hydrolase; KW Magnesium; Manganese; Metal-binding; Mitochondrion; Phosphoprotein; KW Polymorphism; Protein phosphatase; Reference proteome; KW Transit peptide. FT TRANSIT 1 29 Mitochondrion. FT CHAIN 30 372 Protein phosphatase 1K, mitochondrial. FT /FTId=PRO_0000278208. FT DOMAIN 93 346 PP2C-like. FT METAL 127 127 Magnesium. FT METAL 128 128 Magnesium; via carbonyl oxygen. FT METAL 337 337 Magnesium. FT MOD_RES 248 248 Phosphoserine (By similarity). FT VAR_SEQ 148 150 DLL -> YVQ (in isoform 3). FT /FTId=VSP_023156. FT VAR_SEQ 151 372 Missing (in isoform 3). FT /FTId=VSP_023157. FT VAR_SEQ 181 233 ATLLTSGTTATVALLRDGIELVVASVGDSRAILCRKGKPMK FT LTIDHTPERKDE -> ENCAWSAALDLEPVDTICGASVERE FT ICLILSQVKESSGSYPGLREGSHISLSH (in isoform FT 2). FT /FTId=VSP_023158. FT VAR_SEQ 234 372 Missing (in isoform 2). FT /FTId=VSP_023159. FT VARIANT 26 26 R -> H. FT /FTId=VAR_069736. FT VARIANT 94 94 N -> K (in dbSNP:rs17853762). FT /FTId=VAR_030691. FT VARIANT 321 321 E -> K (in dbSNP:rs35523553). FT /FTId=VAR_050621. FT MUTAGEN 298 298 D->A: Loss of activity. FT CONFLICT 17 17 V -> A (in Ref. 3; AAX77016). FT CONFLICT 194 194 L -> I (in Ref. 3; AAX77016). FT CONFLICT 211 211 A -> V (in Ref. 9; AAH20850). FT CONFLICT 264 264 I -> V (in Ref. 5; BAB70790). FT HELIX 92 94 FT STRAND 96 100 FT STRAND 103 106 FT STRAND 109 115 FT STRAND 117 131 FT HELIX 133 149 FT TURN 150 152 FT HELIX 156 176 FT HELIX 183 185 FT STRAND 190 196 FT TURN 197 199 FT STRAND 200 208 FT STRAND 210 215 FT STRAND 218 221 FT HELIX 231 239 FT STRAND 244 246 FT STRAND 252 254 FT TURN 255 257 FT HELIX 267 269 FT TURN 270 273 FT STRAND 279 284 FT TURN 287 289 FT STRAND 290 296 FT HELIX 298 301 FT HELIX 306 314 FT STRAND 316 318 FT HELIX 319 332 FT STRAND 339 345 SQ SEQUENCE 372 AA; 40997 MW; 9DD37EEC0EAD3313 CRC64; MSTAALITLV RSGGNQVRRR VLLSSRLLQD DRRVTPTCHS STSEPRCSRF DPDGSGSPAT WDNFGIWDNR IDEPILLPPS IKYGKPIPKI SLENVGCASQ IGKRKENEDR FDFAQLTDEV LYFAVYDGHG GPAAADFCHT HMEKCIMDLL PKEKNLETLL TLAFLEIDKA FSSHARLSAD ATLLTSGTTA TVALLRDGIE LVVASVGDSR AILCRKGKPM KLTIDHTPER KDEKERIKKC GGFVAWNSLG QPHVNGRLAM TRSIGDLDLK TSGVIAEPET KRIKLHHADD SFLVLTTDGI NFMVNSQEIC DFVNQCHDPN EAAHAVTEQA IQYGTEDNST AVVVPFGAWG KYKNSEINFS FSRSFASSGR WA //