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Human protein phosphatase 2CHuman protein phosphatase 2C

Quartenary structure of human protein phosphatase PP2Cm with Mg(II) (PDB ID 4DA1)

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Protein Phosphatases 2C are essencial enzymes involved in the regulation of several signaling pathways of branched-chain α-ketoacid dehydrogenase complex (BCKDC) by phosphorylation/dephosphorylation. The PP2C Family are Mg²⁺ and Mn²⁺ dependent monomeric proteins with two characteristic structural domains: a catalytic domain N-terminal with six alpha-helices, and a C-terminal region with three alpha-helices. The multienzyme complex uses numerous copies of three enzymes as major building blocks E1, E2 and E3. A dihydrolipoyl transacylase (E2) forms the core of the complex with 24 copies in octahedral symmetry.

The human branched-chain α-ketoacid dehydrogenase complex ser/thr phosphatase, PP2Cm, (BDP) is attached to the E2 core through non-covalent bonds. PP2Cm is distinguished from other groups of phosphatases by its structural distinction, absolute requirement for divalent cation, the catalytic domain and shows Mn²⁺/Mg²⁺ dependent phosphatase activity. PP2Cm structure has two central antiparallel beta sheets that are flanked by alpha helices and the is located at one end of the beta-sheet sandwich containing two coordenated by residues. At high levels of branched-chain ketoacids PP2Cm dephosphorylates Ser-337 and activates mitochondrial BCKDC complex by associating with the E2 component of the complex. The water molecules at the binuclear metal centre coordinate the phosphate group of the substrate, each ion is hexa-coordinated by from water, providing a nucleophile and general acid in the dephosphorylation reaction, and Arg33 creates a local positive electrostatic potential on the protein for recognition of the phosphate group of the substrate. The nucleophile is the metal-bridging water molecule which could attack the phosphorus atom in an S_N2 mechanism. Coordination to two Mg²⁺ ions may stabilize the morenucleophilic hydroxide ion species. Other ions such as Ca²⁺, Zn²⁺ and Ni²⁺ inactivate the enzyme by competitively inhibiting Mn²⁺ or Mg²⁺ binding.

branched-chain α-ketoacid dehydrogenase complexbranched-chain α-ketoacid dehydrogenase complex

The human branched-chain α-ketoacid dehydrogenase (BCKD) complex is part of the mitochondrial α-ketoacid dehydrogenase complex family. Their structure consists of numerous copies of three enzymes E1, E2 and E3. A forms the core of the complex with 24 copies in octahedral symmetry. Copies of the , and copies of the. In some types of (BCKDC) that are two regulatory enzymes proteins and that are attached to the E2 core through non-covalent bonds.

References, for further information on PP2CmReferences, for further information on PP2Cm

Ævarsson, A. et all "Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease", CellPress. [1].
Wynn, R. M. et all "Structure, function and assembly of mammalian branched-chain α-ketoacid dehydrogenase complex", Alpha-Keto Acid Dehydrogenase Complexes. [2]
Lu, G. et all "Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells", The Journal of clinical investigation 119(6):1678-87. [3].
Pan, B. F et all "Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells [4]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Vishal Bhoir, Marta Roldan Lazaro, Cristina Benito, Alexsandra Tifane Santos do Nascimento, Student

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-The androgen receptor (AR) belongs to the steroid hormone group nuclear receptor family with the estrogen, progesterone, glucocorticoid and mineralcorticoid receptor.
+== Human protein phosphatase 2C ==
-AR mediate the actions of testosterone (T) and a more biologically active form, 5α-dihydrotestosterone (DHT), which are the male sex hormones required for development of the male reproductive system and secondary sexual characteristics. This receptor, located on the X chromosome, is expressed in a diverse range of tissues, because they have significant biological actions in many systems <ref>PMID: 27057074</ref>. There are other androgens that bind with much less potency than T and DHT such as androstenedione, androstenediol, and dehydroepiandrosterone (DHEA) <ref>PMID: 36376977 </ref>.
-=Structure=
+<Structure load='2IQ1' size='350' frame='true' align='right' caption='Quartenary structure of human protein phosphatase PP2Cm with Mg(II) (PDB ID 4DA1)' scene='Insert optional scene name here' /> Protein Phosphatases 2C are essencial enzymes involved in the regulation of several signaling pathways of branched-chain α-ketoacid dehydrogenase complex (BCKDC) by phosphorylation/dephosphorylation. The PP2C Family are Mg<sup>2+</sup> and Mn<sup>2+</sup> dependent monomeric proteins with two characteristic structural domains: a catalytic domain N-terminal with six alpha-helices, and a C-terminal region with three alpha-helices. The multienzyme complex uses numerous copies of three enzymes as major building blocks E1, E2 and E3. A dihydrolipoyl transacylase (E2) forms the core of the complex with 24 copies in octahedral symmetry.
+The human branched-chain α-ketoacid dehydrogenase complex ser/thr phosphatase, PP2Cm, (BDP) is attached to the E2 core through non-covalent bonds. PP2Cm is distinguished from other groups of phosphatases by its structural distinction, absolute requirement for divalent cation, the <scene name='32/32/Protein_pp2cm_with_mgii/7'>beta-sheet sandwich</scene> catalytic domain and shows Mn<sup>2+</sup>/Mg<sup>2+</sup> dependent phosphatase activity. PP2Cm structure has two central antiparallel beta sheets that are flanked by alpha helices and the <scene name='32/32/Protein_pp2cm_with_mgii/4'>active site</scene> is located at one end of the beta-sheet sandwich containing two <scene name='32/32/Protein_pp2cm_with_mgii/6'>magnesium ions</scene> coordenated by <scene name='32/32/Protein_pp2cm_with_mgii/5'>Asp-109, Asp-208, Asp-298, and Asp-337</scene> residues.
+At high levels of branched-chain ketoacids PP2Cm dephosphorylates Ser-337 and activates mitochondrial BCKDC complex by associating with the E2 component of the complex.
+The water molecules at the binuclear metal centre coordinate the phosphate group of the substrate, each ion is hexa-coordinated by <scene name='32/32/Protein_pp2cm_with_mgii/8'>oxygen atoms</scene> from water, providing a nucleophile and general acid in the dephosphorylation reaction, and Arg33 creates a local positive electrostatic potential on the protein for recognition of the phosphate group of the substrate. The nucleophile is the metal-bridging water molecule which could attack the phosphorus atom in an S<sub>N</sub>2 mechanism. Coordination to two Mg<sup>2+</sup> ions may stabilize the morenucleophilic hydroxide ion species. Other ions such as Ca<sup>2+</sup>, Zn<sup>2+</sup> and Ni<sup>2+</sup> inactivate the enzyme by competitively inhibiting Mn<sup>2+</sup> or Mg<sup>2+</sup> binding.
+== branched-chain α-ketoacid dehydrogenase complex ==
+The human branched-chain α-ketoacid dehydrogenase (BCKD) complex is part of the mitochondrial α-ketoacid dehydrogenase complex family. Their structure consists of numerous copies of three enzymes E1, E2 and E3. A <scene name='32/32/E2b/1'> dihydrolipoyl transacylase (E2)</scene> forms the core
+of the complex with 24 copies in octahedral symmetry. Copies of the <scene name='32/32/E1/1'> α-ketoacid dehydrogenase (E1)</scene>, and copies of the<scene name='32/32/E3/2'> dihydrolipoamide dehydrogenase (E3)</scene>. In some types of (BCKDC) that are two regulatory enzymes proteins <scene name='32/32/Kinase/1'> protein kinase</scene> and <scene name='32/32/Phosphatase/1'> protein phosphatase</scene> that are attached to the E2 core through non-covalent bonds.
+==References, for further information on PP2Cm==
+* Ævarsson, A. ''et all'' "Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease", CellPress. [https://www.sciencedirect.com/science/article/pii/S0969212600001052].
+* Wynn, R. M. ''et all'' "Structure, function and assembly of mammalian branched-chain α-ketoacid dehydrogenase complex", Alpha-Keto Acid Dehydrogenase Complexes. [https://link.springer.com/chapter/10.1007/978-3-0348-8981-0_7]
-<StructureSection load='3b5r' size='350' side='right' caption='AR' scene=''>
+* Lu, G. ''et all'' "Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells", The Journal of clinical investigation 119(6):1678-87. [https://www.researchgate.net/publication/24398300_Protein_phosphatase_2Cm_is_a_critical_regulator_of_branched-chain_amino_acid_catabolism_in_mice_and_cultured_cells].
+* Pan, B. F ''et all'' "Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816230/]
-<scene name='85/857155/H12_androgen_receptor/1'>H12</scene>
-<scene name='85/857155/Bicatulamide_in_ar/1'>bicatulamide</scene>
-</StructureSection>