Structural and biochemical studies on the chromo-barrel domain of male specific lethal 3 (MSL3) reveal a binding preference for mono- or dimethyllysine 20 on histone H4 |
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Authors: | Moore Stanley A Ferhatoglu Yurdagul Jia Yunhua Al-Jiab Rami A Scott Maxwell J |
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Affiliation: | Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. stan.moore@usask.ca |
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Abstract: | We have determined the human male specific lethal 3 (hMSL3) chromo-barrel domain structure by x-ray crystallography to a resolution of 2.5 Å (r = 0.226, Rfree = 0.270). hMSL3 contains a canonical methyllysine binding pocket made up of residues Tyr-31, Phe-56, Trp-59, and Trp-63. A six-residue insertion between strands β1 and β2 of the hMSL3 chromo-barrel domain directs the side chain of Glu-21 into the methyllysine binding pocket where it hydrogen bonds to the NH group of a bound cyclohexylamino ethanesulfonate buffer molecule, likely mimicking interactions with a histone tail dimethyllysine residue. In vitro binding studies revealed that both the human and Drosophila MSL3 chromo-barrel domains bind preferentially to peptides representing the mono or dimethyl isoform of lysine 20 on the histone H4 N-terminal tail (H4K20Me1 or H4K20Me2). Mutation of Tyr-31 to Ala in the hMSL3 methyllysine-binding cage resulted in weaker in vitro binding to H4K20Me1. The same mutation in the msl3 gene compromised male survival in Drosophila. Combined mutation of Glu-21 and Pro-22 to Ala in hMSL3 resulted in slightly weaker in vitro binding to H4K20Me1, but the corresponding msl3 mutation had no effect on male survival in Drosophila. We propose MSL3 plays an important role in targeting the male specific lethal complex to chromatin in both humans and flies by binding to H4K20Me1. Binding studies on the related dMRG15 chromo-barrel domain revealed that MRG15 prefers binding to H4K20Me3. |
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Keywords: | Chromatin Regulation Crystal Structure Epigenetics Gene Regulation Histone Methylation Chromo-barrel Domain Drosophila Dosage Compensation H4K20 MRG15 MSL3 |
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