ID   PPM1K_BOVIN             Reviewed;         372 AA.
AC   Q2PC20; Q17R15; Q2PC19;
DT   20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT   07-FEB-2006, sequence version 1.
DT   24-JAN-2024, entry version 116.
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   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC   STRAIN=Holstein;
RA   Seroussi E.;
RL   Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   STRAIN=Hereford; TISSUE=Hypothalamus;
RG   NIH - Mammalian Gene Collection (MGC) project;
RL   Submitted (JUN-2006) 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-347 (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. Regulates
CC       Ca(2+)-induced opening of mitochondrial transition pore and apoptotic
CC       cell death (By similarity). {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   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q2PC20-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q2PC20-2; Sequence=VSP_023155;
CC   -!- SIMILARITY: Belongs to the PP2C family. {ECO:0000305}.
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DR   EMBL; AJ871967; CAI44748.1; -; mRNA.
DR   EMBL; AJ871968; CAI44749.1; -; mRNA.
DR   EMBL; BC118079; AAI18080.1; -; mRNA.
DR   RefSeq; NP_001039939.1; NM_001046474.2.
DR   RefSeq; XP_005207855.1; XM_005207798.3. [Q2PC20-1]
DR   AlphaFoldDB; Q2PC20; -.
DR   SMR; Q2PC20; -.
DR   STRING; 9913.ENSBTAP00000007563; -.
DR   PaxDb; 9913-ENSBTAP00000007563; -.
DR   Ensembl; ENSBTAT00000007563.4; ENSBTAP00000007563.3; ENSBTAG00000005754.4. [Q2PC20-1]
DR   GeneID; 540329; -.
DR   KEGG; bta:540329; -.
DR   CTD; 152926; -.
DR   VEuPathDB; HostDB:ENSBTAG00000005754; -.
DR   eggNOG; KOG0698; Eukaryota.
DR   GeneTree; ENSGT00940000156633; -.
DR   HOGENOM; CLU_013173_1_3_1; -.
DR   InParanoid; Q2PC20; -.
DR   OMA; CHTHMKK; -.
DR   OrthoDB; 202023at2759; -.
DR   TreeFam; TF354344; -.
DR   Reactome; R-BTA-70895; Branched-chain amino acid catabolism.
DR   Proteomes; UP000009136; Chromosome 6.
DR   Bgee; ENSBTAG00000005754; Expressed in cardiac ventricle and 109 other cell types or tissues.
DR   GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR   GO; GO:0004722; F:protein serine/threonine phosphatase activity; IBA:GO_Central.
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.
PE   2: Evidence at transcript level;
KW   Alternative splicing; Hydrolase; 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..372
FT                   /note="Protein phosphatase Mn(2+)-dependent 1K"
FT                   /id="PRO_0000278207"
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:0000250|UniProtKB:Q8BXN7"
FT   VAR_SEQ         106..153
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.1"
FT                   /id="VSP_023155"
FT   CONFLICT        365
FT                   /note="F -> I (in Ref. 2; AAI18080)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   372 AA;  41151 MW;  5A8536B6E2F78090 CRC64;
     MSTAALLTLV RSGGNQVRRR VLLRARGLQD DRWVMPTCHS STSEPKWSRF DPDGSGRPAT
     WDNFGIWDNR LEEPILLPPS IKYGKPIPKV SLQNVGSASQ IGKRKENEDR FGFAQLTNEV
     LYFAVYDGHG GPAAADFCHT HMEKCILDLL PKEENLETVL TLAFLEIDKT FARHAHLSAD
     ATLLTSGTTA TVALLRDGIE LVIASVGDSR AILCRKGKPM KLTIDHTPER KDEKERIKKC
     GGFVAWNSLG QPHVNGRLAM TRSLGDLDLK TSGVIAEPET KRIKLHHADD SFLVLTTDGI
     NFMVNSQEIC DFVNQCHDPN EAAHAVTEQA IQYGTEDNTT AVVVPFGAWG KYKNSEITFS
     FSRSFASSGR WA
//