title: Investigation of the β-sheet interactions between dHP1 chromodomain and histone 3.
abstract: Methylated lysine 9 on the histone 3 (H3) tail recruits heterochromatin protein 1 from Drosophila (dHP1) via its chromodomain and results in gene silencing. The dHP1 chromodomain binds H3 K9Me3 with an aromatic cage surrounding the trimethyllysine. The sequence selectivity of binding comes from insertion of the histone tail between two β-strands of the chromodomain to form a three-stranded β-sheet. Herein, we investigated the sequence selectivity provided by the β-sheet interactions and how those interactions compare to other model systems. Residue Thr6 of the histone tail forms cross-strand interactions with Ala25 and Asp62 of the chromodomain. Each of these three residues was substituted for amino acids known to have high β-sheet propensities and/or to form favorable side chain-side chain (SC-SC) interactions in β-sheets, including hydrophobic, H-bonding, and aromatic interactions. We found that about 50% of the chromodomain mutants resulted in equal or tighter binding to the histone tail and about 25% of the histone tail mutants provided tighter binding compared to that of the native histone tail sequence. These studies provide novel insights into the sequence selectivity of the dHP1 chromodomain for the histone tail and relates the information gleaned from model systems and statistical studies to β-sheet-mediated protein-protein interactions. Moreover, this work suggests that the development of designer histone-chromodomain pairs for chemical biology applications is feasible.
authors: Department of Chemistry, CB 3290, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors: Robyn J
authors: RJ
authors: Eisert
authors: Department of Chemistry, CB 3290, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors: Sarah A
authors: SA
authors: Kennedy
authors: Department of Chemistry, CB 3290, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors: Marcey L
authors: ML
authors: Waters
mesh_terms: D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry* / Q000235:genetics; D002942:Circular Dichroism; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics; D005454:Fluorescence Polarization; D006657:Histones / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D006657:Histones; C452193:heterochromatin protein 1, Drosophila