Structural insights for MPP8 chromodomain interaction with histone H3 lysine 9: potential effect of phosphorylation on methyl-lysine binding

• Type of Material: Article
• Authors: Yanqi Chang, Emory University; John Horton, Emory University; Mark T. Bedford, University of Texas; Xing Zhang, Emory University; Xiaodong Cheng, Emory University
• Language: English
• Date: 2011-05-20
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jmb.2011.03.018
• Title of Journal or Parent Work: Journal of Molecular Biology
• ISSN: 0022-2836
• Volume: 408
• Issue: 5
• Start Page: 807
• End Page: 814
• Grant/Funding Information: Use of the APS is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.; This work was supported by grants GM068680 to X.C. from the US National Institutes of Health.; The Northeastern Collaborative Access Team beamline APS-24-ID-E is supported by award RR-15301 from the National Center for Research Resources at the National Institutes of Health.; M.T.B. is supported by NIH grant number DK62248 and, in part, by institutional grant NIEHS ES07784.; X.C. is a Georgia Research Alliance Eminent Scholar.
• Keywords: methyl-lysine binding; X-ray crystallography; epigenetics; MPP8 phosphorylation
• Research Categories: Biology, Molecular; Chemistry, Biochemistry

Abstract

M phase phosphoprotein 8 (MPP8) harbors a N-terminal chromodomain and a C-terminal ankyrin repeat domain. MPP8, via its chromodomain, binds histone H3 peptide tri- or di-methylated at lysine 9 (H3K9me3/2) in submicromolar affinity. We determined the crystal structure of MPP8 chromodomain in complex with H3K9me3 peptide. MPP8 interacts with at least six histone H3 residues from glutamine 5 to serine 10, enabling its ability to distinguish lysine 9 containing peptide (QTARKS) from that of lysine 27 (KAARKS), both sharing the ARKS sequence. A partial hydrophobic cage with three aromatic residues (Phe59, Trp80, Tyr83) and one aspartate (Asp87) encloses the methylated lysine 9. MPP8 has been reported to be phosphorylated in vivo, including the cage residue Tyr83 and the succeeding Thr84 and Ser85. Modeling a phosphate group onto the side chain hydroxyl oxygen of Tyr83 suggests the negatively charged phosphate group could enhance the binding of positively charged methyl-lysine or create a regulatory signal by allowing or inhibiting binding of other protein(s).