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== Human protein phosphatase 2C == | |||
== | <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] | |||
* 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/] | |||