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Proline-Directed Androgen Receptor Phosphorylation.

Gao Y, Chen S - J Mol Genet Med (2013)

Bottom Line: The androgen receptor (AR) has been identified for decades and mediates essential steroid functions.This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor.The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School 330 Brookline, MA 02115, USA.

ABSTRACT

The androgen receptor (AR) has been identified for decades and mediates essential steroid functions. Like most of biological molecules, AR functional activities are modulated by post-translational modifications. This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor. The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

No MeSH data available.


Theoretical and computational characterization of human androgen receptor (hAR) phosphorylation.(A) hAR amino acid linear organization indicated of structural domains and proline(Pro)-directed phosphorylable residues (GenBank: M20132.1); (B) Motif Scan Graphic analysis ofhAR subjected to Pro-directed Ser/Pro kinase (Pro_ST_Kin or Pro_), Acid Ser/Pro kinase (Acid_ST_Kin or Acid_); and Baso Ser/Pro kinase (Baso_ST_Kin, or Baso_) (http://scansite.mit.edu); (C) Phosphorylation analysis of hAR by the DISorder-enhanced PHOSphorylation predictor (DISPHOS, http://www.ist.temple.edu/DISPHOS) program.
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Figure 1: Theoretical and computational characterization of human androgen receptor (hAR) phosphorylation.(A) hAR amino acid linear organization indicated of structural domains and proline(Pro)-directed phosphorylable residues (GenBank: M20132.1); (B) Motif Scan Graphic analysis ofhAR subjected to Pro-directed Ser/Pro kinase (Pro_ST_Kin or Pro_), Acid Ser/Pro kinase (Acid_ST_Kin or Acid_); and Baso Ser/Pro kinase (Baso_ST_Kin, or Baso_) (http://scansite.mit.edu); (C) Phosphorylation analysis of hAR by the DISorder-enhanced PHOSphorylation predictor (DISPHOS, http://www.ist.temple.edu/DISPHOS) program.

Mentions: The AR molecule is structurally organized into distinct domains: the N-terminal domain (NTD) that has a potent activation function 1 (AF-1), DNA-binding domain (DBD), hinge domain (H), and ligand-binding domain (LBD) that binds to androgens and has a modest activation function 2 (AF-2) (Figure 1A). The AR protein shares highly structural similarities in the DBD and LBD with other steroid nuclear receptor family members, such as glucocorticoids receptor (GR), mineral corticoid receptor (MR), and progesterone receptor (PR). However, its NTD and hinge regions are unique and structurally disordered, and share marked diversity among family members. The NTD and hinge domain are also less conservative than the DBD and LBD among ARs from different species. Functionally, these distinct domains confer activities such as N-to-C interactions, DNA loading, antiparallel dimerization, and recruitment of cofactors. The AR proteins are also subjected to multiple post-translational modifications such as acetylation, methylation, ubiquitination and sumoylation. This review will be focused on AR phosphorylation, with emphasis on proline (Pro)-directed phosphorylation.


Proline-Directed Androgen Receptor Phosphorylation.

Gao Y, Chen S - J Mol Genet Med (2013)

Theoretical and computational characterization of human androgen receptor (hAR) phosphorylation.(A) hAR amino acid linear organization indicated of structural domains and proline(Pro)-directed phosphorylable residues (GenBank: M20132.1); (B) Motif Scan Graphic analysis ofhAR subjected to Pro-directed Ser/Pro kinase (Pro_ST_Kin or Pro_), Acid Ser/Pro kinase (Acid_ST_Kin or Acid_); and Baso Ser/Pro kinase (Baso_ST_Kin, or Baso_) (http://scansite.mit.edu); (C) Phosphorylation analysis of hAR by the DISorder-enhanced PHOSphorylation predictor (DISPHOS, http://www.ist.temple.edu/DISPHOS) program.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389684&req=5

Figure 1: Theoretical and computational characterization of human androgen receptor (hAR) phosphorylation.(A) hAR amino acid linear organization indicated of structural domains and proline(Pro)-directed phosphorylable residues (GenBank: M20132.1); (B) Motif Scan Graphic analysis ofhAR subjected to Pro-directed Ser/Pro kinase (Pro_ST_Kin or Pro_), Acid Ser/Pro kinase (Acid_ST_Kin or Acid_); and Baso Ser/Pro kinase (Baso_ST_Kin, or Baso_) (http://scansite.mit.edu); (C) Phosphorylation analysis of hAR by the DISorder-enhanced PHOSphorylation predictor (DISPHOS, http://www.ist.temple.edu/DISPHOS) program.
Mentions: The AR molecule is structurally organized into distinct domains: the N-terminal domain (NTD) that has a potent activation function 1 (AF-1), DNA-binding domain (DBD), hinge domain (H), and ligand-binding domain (LBD) that binds to androgens and has a modest activation function 2 (AF-2) (Figure 1A). The AR protein shares highly structural similarities in the DBD and LBD with other steroid nuclear receptor family members, such as glucocorticoids receptor (GR), mineral corticoid receptor (MR), and progesterone receptor (PR). However, its NTD and hinge regions are unique and structurally disordered, and share marked diversity among family members. The NTD and hinge domain are also less conservative than the DBD and LBD among ARs from different species. Functionally, these distinct domains confer activities such as N-to-C interactions, DNA loading, antiparallel dimerization, and recruitment of cofactors. The AR proteins are also subjected to multiple post-translational modifications such as acetylation, methylation, ubiquitination and sumoylation. This review will be focused on AR phosphorylation, with emphasis on proline (Pro)-directed phosphorylation.

Bottom Line: The androgen receptor (AR) has been identified for decades and mediates essential steroid functions.This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor.The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School 330 Brookline, MA 02115, USA.

ABSTRACT

The androgen receptor (AR) has been identified for decades and mediates essential steroid functions. Like most of biological molecules, AR functional activities are modulated by post-translational modifications. This review is focused on the reported activities and significance of AR phosphorylation, with particular emphasis on proline-directed serine/threonine phosphorylation that occurs predominantly on the receptor. The marked enrichment of AR phosphorylation in the most diverse N-terminal domain suggests that targeting AR phosphorylation can be synergistic to antagonizing the C-terminal domain by clinical antiandrogens.

No MeSH data available.