Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC.

Abstract

Tallant, C., et al., Structure 23, 80–92, January 6, 2015 http://dx.doi.org/10.1016/j.str.2014.10.017Binding of the chromatin remodeling complex NoRC to RNA complementary to the rDNA promoter mediates transcriptional repression. TIP5, the largest subunit of NoRC, is involved in recruitment to rDNA by interactions with promoter-bound TTF-I, pRNA, and acetylation of H4K16. TIP5 domains that recognize posttranslational modifications on histones are essential for recruitment of NoRC to chromatin, but how these reader modules recognize site-specific histone tails has remained elusive. Here, we report crystal structures of PHD zinc finger and bromodomains from human TIP5 and BAZ2B in free form and bound to H3 and/or H4 histones. PHD finger functions as an independent structural module in recognizing unmodified H3 histone tails, and the bromodomain prefers H3 and H4 acetylation marks followed by a key basic residue, KacXXR. Further low-resolution analyses of PHD-bromodomain modules provide molecular insights into their trans histone tail recognition, required for nucleosome recruitment and transcriptional repression of the NoRC complex.This work was supported by the UK Biotechnology and Biological Sciences Research Council (grants BB/G023123/1 David Phillips Fellowship to A.C. and BB/J001201/1 to A.C.) and a Federation of European Biochemical Societies short-term fellowship (04-11-12-10 to C.T.). We are grateful to Dr. Dimitri Y. Chirgadze of the Crystallographic X-Ray Facility at the Department of Biochemistry, University of Cambridge, and to the technical support at Diamond Light Source Synchrotron Facilities. We acknowledge support from the European Commission FP7 Programme under BioStruct-X (grant agreement 283570) for SAXS data collection at the EMBL (DESY). The SGC is a registered charity (No. 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust (092809/Z/10/Z). E.V. is supported by a European Commission FP7 Marie Curie grant IDPbyNMR (contract 264257). P.F. is supported by a Welcome Trust Career Development Fellowship (095751/Z/11/Z)