ID   PPM1K_PONAB             Reviewed;         327 AA.
AC   Q5R522;
DT   20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT   21-DEC-2004, sequence version 1.
DT   27-MAR-2024, entry version 89.
DE   RecName: Full=Protein phosphatase Mn(2+)-dependent 1K;
DE            EC=3.1.3.16 {ECO:0000250|UniProtKB:Q8N3J5};
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   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;
OS   Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Pongo.
OX   NCBI_TaxID=9601;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain cortex;
RG   The German cDNA consortium;
RL   Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
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-337 (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. Recognizes
CC       phosphosites having SxS or RxxS motifs and strictly depends on Mn(2+)
CC       ions for the phosphatase activity. Regulates Ca(2+)-induced opening of
CC       mitochondrial transition pore and apoptotic cell death (By similarity).
CC       {ECO:0000250|UniProtKB:Q8N3J5}.
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:0000250|UniProtKB:Q8N3J5};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20630;
CC         Evidence={ECO:0000250|UniProtKB:Q8N3J5};
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   -!- SIMILARITY: Belongs to the PP2C family. {ECO:0000305}.
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DR   EMBL; CR861060; CAH93144.1; -; mRNA.
DR   RefSeq; NP_001127635.1; NM_001134163.1.
DR   AlphaFoldDB; Q5R522; -.
DR   SMR; Q5R522; -.
DR   STRING; 9601.ENSPPYP00000016662; -.
DR   Ensembl; ENSPPYT00000039428.1; ENSPPYP00000032199.1; ENSPPYG00000038477.1.
DR   GeneID; 100174714; -.
DR   KEGG; pon:100174714; -.
DR   CTD; 152926; -.
DR   GeneTree; ENSGT00940000156633; -.
DR   InParanoid; Q5R522; -.
DR   OrthoDB; 202023at2759; -.
DR   Proteomes; UP000001595; Chromosome 4.
DR   GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
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; SM00332; PP2Cc; 1.
DR   SUPFAM; SSF81606; PP2C-like; 1.
DR   PROSITE; PS01032; PPM_1; 1.
DR   PROSITE; PS51746; PPM_2; 1.
PE   2: Evidence at transcript level;
KW   Hydrolase; Magnesium; Manganese; Metal-binding; Mitochondrion;
KW   Phosphoprotein; Protein phosphatase; Reference proteome; Transit peptide.
FT   TRANSIT         1..29
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000250"
FT   CHAIN           30..327
FT                   /note="Protein phosphatase Mn(2+)-dependent 1K"
FT                   /id="PRO_0000278210"
FT   DOMAIN          94..327
FT                   /note="PPM-type phosphatase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01082"
FT   REGION          33..55
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          46..61
FT                   /note="Critical for association with the BCKDH complex"
FT                   /evidence="ECO:0000250|UniProtKB:Q8N3J5"
FT   COMPBIAS        33..48
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
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         292
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:0000250|UniProtKB:Q8BXN7"
SQ   SEQUENCE   327 AA;  35960 MW;  A8A52297BD7D0870 CRC64;
     MSTAALITLV RSGGNQVRRR VLLSSRLLQD DRRATPTCHS STSEPRCSRF DPDGSGSPAT
     WDNFGIWDNR IDEPILLPPS IKYGKPIPKI SLENVGCASQ IGKRKENEDR FDFAQLTDEV
     LYFAVYDGHG GPAAADFCHT HMEKCIMDLL PKEKNLETLL TLAFLEIDKA FSSHARLSAD
     ATLLTSGTTA TVALLRDGIE LVVASVGDSR AILCRKGKPM KLTIDHTPER KDEKERIKKC
     GGFVAWNSLG QPHVNGRLAM TRSIGDLDLK TSGVIAEPET KRIKAIQYGT EDNSTAVVVP
     FGAWGKYKNS EINFSFSRSF ASSGRWA
//