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Nucleic Acids Research Advance Access published online on February 11, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn029
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

p160/SRC/NCoA coactivators form complexes via specific interaction of their PAS-B domain with the CID/AD1 domain

Marco Lodrini1, Tobias Münz2, Nicolas Coudevylle3, Christian Griesinger3, Stefan Becker3 and Edith Pfitzner1,2,*

1Georg-Speyer-Haus, Institute for Biomedical Research, Paul-Ehrlich-Straße 42-44, 60596 Frankfurt, 2Friedrich-Schiller-University Jena, Institute of Biochemistry and Biophysics, Philosophenweg 12, 07743 Jena and 3Max Planck Institute for Biophysical Chemistry, Department for NMR-based Structural Biology, Am Faßberg 11, 37077, Göttingen, Germany

*To whom correspondence should be addressed. Tel: +49 3641 949355; Fax: +49 3641 949352; Email: e.pfitzner{at}uni-jena.de

Received September 28, 2007. Revised January 16, 2008. Accepted January 17, 2008.

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.


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