P160/SRC/NCoA coactivators form complexes via specific interaction of their PAS-B domain with the CID/AD1 domain.

Transcriptional activation involves the ordered recruitment of coactivators via direct interactions between distinct binding domains and recognition motifs. The p160/SRC/NCoA coactivator family comprises three members (NCoA-1, -2 and -3), which are organized in multiprotein coactivator complexes. We had identified the PAS-B domain of NCoA-1 as an LXXLL motif binding domain. ...
Here we show that NCoA family members are able to interact with other full-length NCoA proteins via their PAS-B domain and they specifically interact with the CBP-interaction domain (CID/AD1) of NCoA-1. Peptide competition, binding experiments and mutagenesis of LXXLL motifs point at distinct binding motif specificities of the NCoA PAS-B domains. NMR studies of different NCoA-1-PAS-B/LXXLL peptide complexes revealed similar although not identical binding sites for the CID/AD1 and STAT6 transactivation domain LXXLL motifs. In mechanistic studies, we found that overexpression of the PAS-B domain is able to disturb the binding of NCoA-1 to CBP in cells and that a CID/AD1 peptide competes with STAT6 for NCoA-1 in vitro. Moreover, the expression of an endogenous androgen receptor target gene is affected by the overexpression of the NCoA-1 or NCoA-3 PAS-B domains. Our study discloses a new, complementary mechanism for the current model of coactivator recruitment to target gene promoters.
Mesh Terms:
Amino Acid Motifs, Binding, Competitive, CREB-Binding Protein, Cell Line, Histone Acetyltransferases, Humans, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivator 2, Nuclear Receptor Coactivator 3, Protein Interaction Domains and Motifs, Receptors, Cytoplasmic and Nuclear, STAT6 Transcription Factor, Trans-Activators, Transcription Factors, Transcriptional Activation
Nucleic Acids Res.
Date: Apr. 01, 2008
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