Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase

Maojun Yang, Christian B. Gocke, Xuelian Luo, Dominika Borek, Diana R. Tomchick, Mischa Machius, Zbyszek Otwinowski, Hongtao Yu

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

Histone methylation regulates diverse chromatin-templated processes, including transcription. Many transcriptional corepressor complexes contain lysine-specific demethylase 1 (LSD1) and CoREST that collaborate to demethylate mono- and dimethylated H3-K4 of nucleosomes. Here, we report the crystal structure of the LSD1-CoREST complex. LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain. LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface. CoREST SANT2 interacts with DNA. Disruption of the SANT2-DNA interaction diminishes CoREST-dependent demethylation of nucleosomes by LSD1. The shape and dimension of LSD1-CoREST suggest its bivalent binding to nucleosomes, allowing efficient H3-K4 demethylation. This spatially separated, multivalent nucleosome binding mode may apply to other chromatin-modifying enzymes that generally contain multiple nucleosome binding modules.

Original languageEnglish (US)
Pages (from-to)377-387
Number of pages11
JournalMolecular Cell
Volume23
Issue number3
DOIs
StatePublished - Aug 4 2006

Fingerprint

Histone Demethylases
Nucleosomes
Lysine
Chromatin
Catalytic Domain
Co-Repressor Proteins
DNA
human KDM1A protein
Histones
Methylation

Keywords

  • DNA

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase. / Yang, Maojun; Gocke, Christian B.; Luo, Xuelian; Borek, Dominika; Tomchick, Diana R.; Machius, Mischa; Otwinowski, Zbyszek; Yu, Hongtao.

In: Molecular Cell, Vol. 23, No. 3, 04.08.2006, p. 377-387.

Research output: Contribution to journalArticle

@article{6543a38510f8440f8ab75e0d87230f24,
title = "Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase",
abstract = "Histone methylation regulates diverse chromatin-templated processes, including transcription. Many transcriptional corepressor complexes contain lysine-specific demethylase 1 (LSD1) and CoREST that collaborate to demethylate mono- and dimethylated H3-K4 of nucleosomes. Here, we report the crystal structure of the LSD1-CoREST complex. LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain. LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface. CoREST SANT2 interacts with DNA. Disruption of the SANT2-DNA interaction diminishes CoREST-dependent demethylation of nucleosomes by LSD1. The shape and dimension of LSD1-CoREST suggest its bivalent binding to nucleosomes, allowing efficient H3-K4 demethylation. This spatially separated, multivalent nucleosome binding mode may apply to other chromatin-modifying enzymes that generally contain multiple nucleosome binding modules.",
keywords = "DNA",
author = "Maojun Yang and Gocke, {Christian B.} and Xuelian Luo and Dominika Borek and Tomchick, {Diana R.} and Mischa Machius and Zbyszek Otwinowski and Hongtao Yu",
year = "2006",
month = "8",
day = "4",
doi = "10.1016/j.molcel.2006.07.012",
language = "English (US)",
volume = "23",
pages = "377--387",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase

AU - Yang, Maojun

AU - Gocke, Christian B.

AU - Luo, Xuelian

AU - Borek, Dominika

AU - Tomchick, Diana R.

AU - Machius, Mischa

AU - Otwinowski, Zbyszek

AU - Yu, Hongtao

PY - 2006/8/4

Y1 - 2006/8/4

N2 - Histone methylation regulates diverse chromatin-templated processes, including transcription. Many transcriptional corepressor complexes contain lysine-specific demethylase 1 (LSD1) and CoREST that collaborate to demethylate mono- and dimethylated H3-K4 of nucleosomes. Here, we report the crystal structure of the LSD1-CoREST complex. LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain. LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface. CoREST SANT2 interacts with DNA. Disruption of the SANT2-DNA interaction diminishes CoREST-dependent demethylation of nucleosomes by LSD1. The shape and dimension of LSD1-CoREST suggest its bivalent binding to nucleosomes, allowing efficient H3-K4 demethylation. This spatially separated, multivalent nucleosome binding mode may apply to other chromatin-modifying enzymes that generally contain multiple nucleosome binding modules.

AB - Histone methylation regulates diverse chromatin-templated processes, including transcription. Many transcriptional corepressor complexes contain lysine-specific demethylase 1 (LSD1) and CoREST that collaborate to demethylate mono- and dimethylated H3-K4 of nucleosomes. Here, we report the crystal structure of the LSD1-CoREST complex. LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain. LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface. CoREST SANT2 interacts with DNA. Disruption of the SANT2-DNA interaction diminishes CoREST-dependent demethylation of nucleosomes by LSD1. The shape and dimension of LSD1-CoREST suggest its bivalent binding to nucleosomes, allowing efficient H3-K4 demethylation. This spatially separated, multivalent nucleosome binding mode may apply to other chromatin-modifying enzymes that generally contain multiple nucleosome binding modules.

KW - DNA

UR - http://www.scopus.com/inward/record.url?scp=33746435258&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746435258&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2006.07.012

DO - 10.1016/j.molcel.2006.07.012

M3 - Article

C2 - 16885027

AN - SCOPUS:33746435258

VL - 23

SP - 377

EP - 387

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -