Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF Journal Article

   

Authors:	Li, H.; Ilin, S.; Wang, W.; Duncan, E. M.; Wysocka, J.; Allis, C. D.; Patel, D. J.
Article Title:	Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF
Abstract:	Mono-, di- and trimethylated states of particular histone lysine residues are selectively found in different regions of chromatin, thereby implying specialized biological functions for these marks ranging from heterochromatin formation to X-chromosome inactivation and transcriptional regulation. A major challenge in chromatin biology has centred on efforts to define the connection between specific methylation states and distinct biological read-outs impacting on function. For example, histone H3 trimethylated at lysine 4 (H3K4me3) is associated with transcription start sites of active genes, but the molecular 'effectors' involved in specific recognition of H3K4me3 tails remain poorly understood. Here we demonstrate the molecular basis for specific recognition of H3(1-15)K4me3 (residues 1-15 of histone H3 trimethylated at K4) by a plant homeodomain (PHD) finger of human BPTF (bromodomain and PHD domain transcription factor), the largest subunit of the ATP-dependent chromatin-remodelling complex, NURF (nucleosome remodelling factor). We report on crystallographic and NMR structures of the bromodomain-proximal PHD finger of BPTF in free and H3(1-15)K4me3-bound states. H3(1-15)K4me3 interacts through anti-parallel Β-sheet formation on the surface of the PHD finger, with the long side chains of arginine 2 (R2) and K4me3 fitting snugly in adjacent pre-formed surface pockets, and bracketing an invariant tryptophan. The observed stapling role by non-adjacent R2 and K4me3 provides a molecular explanation for H3K4me3 site specificity. Binding studies establish that the BPTF PHD finger exhibits a modest preference for K4me3- over K4me2-containing H3 peptides, and discriminates against monomethylated and unmodified counterparts. Furthermore, we identified key specificity-determining residues from binding studies of H3(1-15)K4me3 with PHD finger point mutants. Our findings call attention to the PHD finger as a previously uncharacterized chromatin-binding module found in a large number of chromatin-associated proteins. © 2006 Nature Publishing Group.
Keywords:	unclassified drug; methylation; mutant protein; protein conformation; protein domain; proteins; chromosomal proteins, non-histone; complex formation; nerve tissue proteins; protein; protein binding; transcription factor; protein interaction; peptide; transcription factors; histone; chromatin; histone h3; nucleic acids; substrate specificity; molecular analysis; nuclear magnetic resonance spectroscopy; dna fingerprinting; models, molecular; crystallography, x-ray; binding sites; homeodomain protein; protein subunit; molecular biology; protein structure; biochemistry; surface plasmon resonance; histones; nuclear magnetic resonance; lysine; chromosomes; arginine; amino acid motifs; tryptophan; transcription initiation site; nuclear magnetic resonance, biomolecular; crystallography; modeling; calorimetry; chemical binding; antigens, nuclear; x-chromosome; nucleosome remodelling factor
Journal Title:	Nature
Volume:	442
Issue:	7098
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2006-07-06
Start Page:	91
End Page:	95
Language:	English
DOI:	10.1038/nature04802
PUBMED:	16728978
PROVIDER:	scopus
PMCID:	PMC4690523
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-33745809637&partnerID=40&md5=dc724cafa1c044081aee382e3392e57e
Notes:	--- - "Cited By (since 1996): 289" - "Export Date: 4 June 2012" - "CODEN: NATUA" - "Source: Scopus"

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