title: Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC.
abstract: Binding 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: European Molecular Biology Laboratory, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22603 Hamburg, Germany.
authors.forename: Erica
authors.initials: E
authors.lastname: Valentini
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Lois
authors.initials: L
authors.lastname: Overvoorde
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Fleur M
authors.initials: FM
authors.lastname: Ferguson
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.affiliation: European Molecular Biology Laboratory, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22603 Hamburg, Germany.
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Electronic address: a.ciulli@dundee.ac.uk.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D000595:Amino Acid Sequence; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017386:Sequence Homology, Amino Acid; D016335:Zinc Fingers; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; C436708:BAZ2A protein, human; D000092468:Bromodomain Containing Proteins