The structure of the cysteine-rich region from human histone-lysine N-methyltransferase EHMT2 (G9a)

Keshia M. Kerchner; Tung Chung Mou; Yizhi Sun; Domniţa Valeria Rusnac; Stephen R. Sprang; Klára Briknarová

doi:10.1016/j.yjsbx.2021.100050

The structure of the cysteine-rich region from human histone-lysine N-methyltransferase EHMT2 (G9a)

Keshia M. Kerchner
, Tung Chung Mou
, Yizhi Sun
, Domniţa Valeria Rusnac
, Stephen R. Sprang
, Klára Briknarová

University of Montana

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Euchromatic histone-lysine N-methyltransferase 1 (EHMT1; G9a-like protein; GLP) and euchromatic histone-lysine N-methyltransferase 2 (EHMT2; G9a) are protein lysine methyltransferases that regulate gene expression and are essential for development and the ability of organisms to change and adapt. In addition to ankyrin repeats and the catalytic SET domain, the EHMT proteins contain a unique cysteine-rich region (CRR) that mediates protein–protein interactions and recruitment of the methyltransferases to specific sites in chromatin. We have determined the structure of the CRR from human EHMT2 by X-ray crystallography and show that the CRR adopts an unusual compact fold with four bound zinc atoms. The structure consists of a RING domain preceded by a smaller zinc-binding motif and an N-terminal segment. The smaller zinc-binding motif straddles the N-terminal end of the RING domain, and the N-terminal segment runs in an extended conformation along one side of the structure and interacts with both the smaller zinc-binding motif and the RING domain. The interface between the N-terminal segment and the RING domain includes one of the zinc atoms. The RING domain is partially sequestered within the CRR and unlikely to function as a ubiquitin ligase.

Original language	English
Article number	100050
Journal	Journal of Structural Biology: X
Volume	5
DOIs	https://doi.org/10.1016/j.yjsbx.2021.100050
State	Published - Jan 2021

Funding

Research reported in this publication was supported by the National Institutes of Health (NIH) (award number P20GM103546). The 600 MHz NMR spectrometer was purchased with funds from the National Science Foundation (award number CHE-0321002) and from the Murdock Charitable Trust. We are grateful to the staff at APS SBC-CAT 19-BM and SSRL 12-2 beamlines for assistance with X-ray crystallographic data collection. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy (DOE) (contract number DE-AC02-76SF00515). The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by NIH (award number P41GM103393). The Structural Biology Center SBC-CAT at the Advanced Photon Source, Argonne National Laboratory is operated by UChicago Argonne, LLC, for the DOE, Office of Biological and Environmental Research (contract number DE-AC02-06CH11357).

Funders	Funder number
CHE-0321002
P20GM103546
DE-AC02-76SF00515
Biological and Environmental Research	P41GM103393, DE-AC02-06CH11357
Argonne National Laboratory

Keywords

Chromatin targeting
Protein interaction
RING domain
X-ray crystallography
Zinc-binding motif

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10.1016/j.yjsbx.2021.100050

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title = "The structure of the cysteine-rich region from human histone-lysine N-methyltransferase EHMT2 (G9a)",

abstract = "Euchromatic histone-lysine N-methyltransferase 1 (EHMT1; G9a-like protein; GLP) and euchromatic histone-lysine N-methyltransferase 2 (EHMT2; G9a) are protein lysine methyltransferases that regulate gene expression and are essential for development and the ability of organisms to change and adapt. In addition to ankyrin repeats and the catalytic SET domain, the EHMT proteins contain a unique cysteine-rich region (CRR) that mediates protein–protein interactions and recruitment of the methyltransferases to specific sites in chromatin. We have determined the structure of the CRR from human EHMT2 by X-ray crystallography and show that the CRR adopts an unusual compact fold with four bound zinc atoms. The structure consists of a RING domain preceded by a smaller zinc-binding motif and an N-terminal segment. The smaller zinc-binding motif straddles the N-terminal end of the RING domain, and the N-terminal segment runs in an extended conformation along one side of the structure and interacts with both the smaller zinc-binding motif and the RING domain. The interface between the N-terminal segment and the RING domain includes one of the zinc atoms. The RING domain is partially sequestered within the CRR and unlikely to function as a ubiquitin ligase.",

keywords = "Chromatin targeting, Protein interaction, RING domain, X-ray crystallography, Zinc-binding motif",

author = "Kerchner, \{Keshia M.\} and Mou, \{Tung Chung\} and Yizhi Sun and Rusnac, \{Domni{\c t}a Valeria\} and Sprang, \{Stephen R.\} and Kl{\'a}ra Briknarov{\'a}",

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AU - Kerchner, Keshia M.

AU - Mou, Tung Chung

AU - Sun, Yizhi

AU - Rusnac, Domniţa Valeria

AU - Sprang, Stephen R.

AU - Briknarová, Klára

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N2 - Euchromatic histone-lysine N-methyltransferase 1 (EHMT1; G9a-like protein; GLP) and euchromatic histone-lysine N-methyltransferase 2 (EHMT2; G9a) are protein lysine methyltransferases that regulate gene expression and are essential for development and the ability of organisms to change and adapt. In addition to ankyrin repeats and the catalytic SET domain, the EHMT proteins contain a unique cysteine-rich region (CRR) that mediates protein–protein interactions and recruitment of the methyltransferases to specific sites in chromatin. We have determined the structure of the CRR from human EHMT2 by X-ray crystallography and show that the CRR adopts an unusual compact fold with four bound zinc atoms. The structure consists of a RING domain preceded by a smaller zinc-binding motif and an N-terminal segment. The smaller zinc-binding motif straddles the N-terminal end of the RING domain, and the N-terminal segment runs in an extended conformation along one side of the structure and interacts with both the smaller zinc-binding motif and the RING domain. The interface between the N-terminal segment and the RING domain includes one of the zinc atoms. The RING domain is partially sequestered within the CRR and unlikely to function as a ubiquitin ligase.

AB - Euchromatic histone-lysine N-methyltransferase 1 (EHMT1; G9a-like protein; GLP) and euchromatic histone-lysine N-methyltransferase 2 (EHMT2; G9a) are protein lysine methyltransferases that regulate gene expression and are essential for development and the ability of organisms to change and adapt. In addition to ankyrin repeats and the catalytic SET domain, the EHMT proteins contain a unique cysteine-rich region (CRR) that mediates protein–protein interactions and recruitment of the methyltransferases to specific sites in chromatin. We have determined the structure of the CRR from human EHMT2 by X-ray crystallography and show that the CRR adopts an unusual compact fold with four bound zinc atoms. The structure consists of a RING domain preceded by a smaller zinc-binding motif and an N-terminal segment. The smaller zinc-binding motif straddles the N-terminal end of the RING domain, and the N-terminal segment runs in an extended conformation along one side of the structure and interacts with both the smaller zinc-binding motif and the RING domain. The interface between the N-terminal segment and the RING domain includes one of the zinc atoms. The RING domain is partially sequestered within the CRR and unlikely to function as a ubiquitin ligase.

KW - Chromatin targeting

KW - Protein interaction

KW - RING domain

KW - X-ray crystallography

KW - Zinc-binding motif

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DO - 10.1016/j.yjsbx.2021.100050

M3 - Article

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JO - Journal of Structural Biology: X

JF - Journal of Structural Biology: X

M1 - 100050

ER -

The structure of the cysteine-rich region from human histone-lysine N-methyltransferase EHMT2 (G9a)

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Keywords

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