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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.  
Like members of the nuclear receptor family, the AR consists of three main functional domains which aid in controlling and regulating transcriptional activity.
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.
==Domains==
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.
===N-terminal Domain (NTD)(residues 1-555)===
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.
This region is required for full transcriptional activity <ref>PMID: 24909511 </ref>, because of its necessary presence for LBD activation <ref>PMID: 33076388</ref>. It is the most variable domain, the sequence and lengths of the polyglutamine (CAG) and polyglycine (GGC) repeats are highly variable in the human population. It has been shown that the length of the polyglutamine repeat region affects the folding and structure of this domain, shorter repeats generally impose a higher AR transactivation activity, whereas longer repeats cause reduced activity  <ref>PMID: 24909511 </ref>. In healthy people, one region of the AR gene shows up to 36 repeats of the CAG sequence. Patients with abnormally high numbers of CAG repeats can develop spinal muscular atrophy.
===DNA-binding Domain (DBD) (residues 555-623)===
DBD is a cysteine-rich region that is the most highly conserved one of the steroid hormone nuclear receptor family <ref>PMID: 24909511 </ref>, but it has been shown that binding of selective androgen response elements (AREs) allow the specific activation functions of the AR. They facilitate direct DNA binding of the AR to the promoter and enhancer regions of AR-regulated genes, thereby allowing the activation functions of the N-terminal and ligand binding domains to stimulate or repress the transcription of these genes <ref>PMID: 27057074</ref>.
AR is a dimer, like other steroid receptors, that binds to promoter DNA response elements consisting of two equal, common hexameric half-sites, separated by a 3 base-pair spacer <ref>PMID: 24909511 </ref>'''IMAGEN DEL DÍMERO''', and this domain is critical for AR function, because it plays a role in dimerization and binding of dimerized AR to select motifs on target DNA <ref>PMID: 33076388</ref>.
Each DBD monomer has a core composed of two zinc finger motifs, which consists of four cysteine residues that coordinate a zinc ion <ref>PMID: 24909511 </ref>. The first is closer to the NTD which has the P box, which is identical in all the family, and controls the DNA binding specificity at AREs, located in the regulatory regions of genes <ref>PMID: 33076388</ref>.  
The second zinc finger motif facilitates AR dimerization via the D box. Additionally, a nuclear localization signal (NLS) is localized at the junction between the DBD and the hinge region and it binds to importin-α and facilitates nuclear translocation <ref>PMID: 33076388</ref>. This is because passive transport across the nuclear pore complex has been suggested ranging from 20–40 kDa, in contrast, the AR, which is 110 kDa in size, requires help to be actively transported upon ligand binding <ref>PMID: 24909511 </ref>.
The DBD is linked to the ligand binding domain by a flexible hinge region (residues 623-665), which is a linker poorly conserved. Once in the nucleus, this region also interacts with the DBD to identify specific sequences for AR binding. It controls the AR activation and degradation. Consequently, mutations in the hinge region can lead to enhanced AR potency <ref>PMID: 33076388</ref>.


== 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>

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