Structural Insights into Stimulation of Ash1L's H3K36 Methyltransferase Activity through Mrg15 Binding

Peini Hou; Chang Huang; Chao-Pei Liu; Na Yang; Tianshu Yu; Yuxin Yin; Bing Zhu; Rui-Ming Xu

doi:10.1016/j.str.2019.01.015

Structural Insights into Stimulation of Ash1L's H3K36 Methyltransferase Activity through Mrg15 Binding

Structure. 2019 May 7;27(5):837-845.e3. doi: 10.1016/j.str.2019.01.015. Epub 2019 Feb 28.

Authors

Peini Hou¹, Chang Huang², Chao-Pei Liu², Na Yang³, Tianshu Yu⁴, Yuxin Yin⁴, Bing Zhu⁵, Rui-Ming Xu⁶

Affiliations

¹ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10049, China.
² National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
³ State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China.
⁴ Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing 100191, China.
⁵ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10049, China. Electronic address: zhubing@ibp.ac.cn.
⁶ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10049, China. Electronic address: rmxu@ibp.ac.cn.

PMID: 30827843
DOI: 10.1016/j.str.2019.01.015

Abstract

The evolutionarily conserved Trithorax group protein Ash1 is a SET domain histone methyltransferase that mono- and dimethylates lysine 36 of histone H3 (H3K36). Ash1 forms a complex with Mrg15 and Nurf55, and the binding of Mrg15 greatly stimulates the catalytic activity of Ash1, yet the underlying molecular mechanisms remain unknown. Here we report the crystal structure of the tandem Mrg15-interacting and SET domains of human Ash1L in complex with Mrg15. Ash1L interacts with Mrg15 principally via a segment located N-terminal to the catalytic SET domain. Surprisingly, an autoinhibitory loop in the post-SET region of Ash1L is destabilized on Mrg15 binding despite no direct contact. Dynamics of the autoinhibitory loop can be attributed to subtle structural changes of the S-adenosylmethionine (SAM) binding pocket induced by Mrg15 binding, implicating a mechanism of conformational coupling between SAM and substrate binding sites. The findings broaden the understanding of regulation of H3K36 methyltransferases.

Keywords: Ash1L; Mrg15; SET domain; autoinhibitory loop; crystal structure; histone; methyltransferase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Catalytic Domain
Computer Simulation
Crystallography, X-Ray
DNA-Binding Proteins / chemistry*
Histone-Lysine N-Methyltransferase / chemistry*
Histones / chemistry*
Humans
Hydrogen Bonding
Methylation
Protein Binding
Transcription Factors / chemistry*

Substances

DNA-Binding Proteins
Histones
MORF4L1 protein, human
Transcription Factors
ASH1L protein, human
Histone-Lysine N-Methyltransferase