Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation
Abstract
Histone H3 lysine 36 methylation (H3K36me) is critical for epigenetic regulation and mutations at or near H3K36 are associated with distinct types of cancers. H3K36M dominantly inhibits H3K36me on wild-type histones, whereas H3G34R/V selectively affects H3K36me on the same histone tail. Here we report the crystal structures of SETD2 SET domain in complex with an H3K36M peptide and SAM or SAH. There are large conformational changes in the substrate binding regions of the SET domain, and the K36M residue interacts with the catalytic pocket of SETD2. H3G34 is surrounded by a very narrow tunnel, which excludes larger amino acid side chains. H3P38 is in the trans configuration, and the cis configuration is incompatible with SETD2 binding. Lastly, mutations of H3G34 or H3P38 alleviate the inhibitory effects of H3K36M on H3K36me, demonstrating that the stable interaction of H3K36M with SETD2 is critical for its inhibitory effects.
- Authors:
-
- Columbia Univ., New York, NY (United States)
- Publication Date:
- Research Org.:
- Columbia Univ., New York, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1355913
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 7; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; gene expression; pediatric glioblastoma; H3.3K27M mutation; driver mutations; in-vivo; H3; methyltransferase; inhibition; methionine; reprograms; methylation; X-ray crystallography
Citation Formats
Zhang, Yinglu, Shan, Chun -Min, Wang, Jiyong, Bao, Kehan, Tong, Liang, and Jia, Songtao. Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation. United States: N. p., 2017.
Web. doi:10.1038/srep43906.
Zhang, Yinglu, Shan, Chun -Min, Wang, Jiyong, Bao, Kehan, Tong, Liang, & Jia, Songtao. Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation. United States. https://doi.org/10.1038/srep43906
Zhang, Yinglu, Shan, Chun -Min, Wang, Jiyong, Bao, Kehan, Tong, Liang, and Jia, Songtao. Fri .
"Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation". United States. https://doi.org/10.1038/srep43906. https://www.osti.gov/servlets/purl/1355913.
@article{osti_1355913,
title = {Molecular basis for the role of oncogenic histone mutations in modulating H3K36 methylation},
author = {Zhang, Yinglu and Shan, Chun -Min and Wang, Jiyong and Bao, Kehan and Tong, Liang and Jia, Songtao},
abstractNote = {Histone H3 lysine 36 methylation (H3K36me) is critical for epigenetic regulation and mutations at or near H3K36 are associated with distinct types of cancers. H3K36M dominantly inhibits H3K36me on wild-type histones, whereas H3G34R/V selectively affects H3K36me on the same histone tail. Here we report the crystal structures of SETD2 SET domain in complex with an H3K36M peptide and SAM or SAH. There are large conformational changes in the substrate binding regions of the SET domain, and the K36M residue interacts with the catalytic pocket of SETD2. H3G34 is surrounded by a very narrow tunnel, which excludes larger amino acid side chains. H3P38 is in the trans configuration, and the cis configuration is incompatible with SETD2 binding. Lastly, mutations of H3G34 or H3P38 alleviate the inhibitory effects of H3K36M on H3K36me, demonstrating that the stable interaction of H3K36M with SETD2 is critical for its inhibitory effects.},
doi = {10.1038/srep43906},
journal = {Scientific Reports},
number = ,
volume = 7,
place = {United States},
year = {Fri Mar 03 00:00:00 EST 2017},
month = {Fri Mar 03 00:00:00 EST 2017}
}
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