( Sivulöytö kun seulon ZBTB -ryhmän(C2H2) sinkkiproteiineja ) TMPRSS2 mainitaan COVID-19 pandemian aikana tekijänä S- piikin infektioprosessissa.
- Functional screening of FxxLF-like peptide motifs identifies SMARCD1/BAF60a as an androgen receptor cofactor that modulates TMPRSS2 expression. van de Wijngaart DJ, et al. Mol Endocrinol, 2009 Nov. PMID 19762545, Free PMC Article
Mol Endocrinol. 2009 Nov;23(11):1776-86. doi: 10.1210/me.2008-0280. Epub 2009 Sep 17.
Abstract
Androgen
receptor (AR) transcriptional activity is tightly regulated by
interacting cofactors and cofactor complexes. The best described
cofactor interaction site in the AR is the hormone-induced coactivator
binding groove in the ligand-binding domain, which serves as a
high-affinity docking site for FxxLF-like motifs. This study aimed at
identifying novel AR cofactors by in silico selection and functional
screening of FxxLF-like peptide motifs.
Candidate interacting motifs were selected from a proteome-wide screening and from a supervised screening focusing on components of protein complexes involved in transcriptional regulation. Of the 104 peptides tested, 12 displayed moderate to strong in vivo hormone-dependent interactions with AR. For three of these, ZBTB16/PLZF, SMARCA4/BRG1, and SMARCD1/BAF60a, the full-length protein was tested for interaction with AR. Of these, BAF60a, a subunit of the SWI/SNF chromatin remodeling complex, displayed hormone-dependent interactions with AR through its FxxFF motif. Vice versa, recruitment of BAF60a by the AR required an intact coactivator groove. BAF60a depletion by small interfering RNA in LNCaP cells demonstrated differential effects on expression of endogenous AR target genes. AR-driven expression of TMPRSS2 was almost completely blocked by BAF60a small interfering RNA. In summary, our data demonstrate that BAF60a directly interacts with the coactivator groove in the AR ligand-binding domain via its FxxFF motif, thereby selectively activating specific AR-driven promoters.
Candidate interacting motifs were selected from a proteome-wide screening and from a supervised screening focusing on components of protein complexes involved in transcriptional regulation. Of the 104 peptides tested, 12 displayed moderate to strong in vivo hormone-dependent interactions with AR. For three of these, ZBTB16/PLZF, SMARCA4/BRG1, and SMARCD1/BAF60a, the full-length protein was tested for interaction with AR. Of these, BAF60a, a subunit of the SWI/SNF chromatin remodeling complex, displayed hormone-dependent interactions with AR through its FxxFF motif. Vice versa, recruitment of BAF60a by the AR required an intact coactivator groove. BAF60a depletion by small interfering RNA in LNCaP cells demonstrated differential effects on expression of endogenous AR target genes. AR-driven expression of TMPRSS2 was almost completely blocked by BAF60a small interfering RNA. In summary, our data demonstrate that BAF60a directly interacts with the coactivator groove in the AR ligand-binding domain via its FxxFF motif, thereby selectively activating specific AR-driven promoters.
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