Cryo-EM structure of the human MLL1 core complex bound to the nucleosome

Sang Ho Park; Alex Ayoub; Young-Tae Lee; Jing Xu; Hanseong Kim; Wei Zheng; Biao Zhang; Liang Sha; Sojin An; Yang Zhang; Michael A Cianfrocco; Min Su; Yali Dou; Uhn-Soo Cho

doi:10.1038/s41467-019-13550-2

Cryo-EM structure of the human MLL1 core complex bound to the nucleosome

Nat Commun. 2019 Dec 5;10(1):5540. doi: 10.1038/s41467-019-13550-2.

Authors

Sang Ho Park¹, Alex Ayoub², Young-Tae Lee², Jing Xu², Hanseong Kim¹, Wei Zheng³, Biao Zhang³, Liang Sha², Sojin An¹, Yang Zhang^{1

3}, Michael A Cianfrocco^{1

4}, Min Su⁴, Yali Dou^{5

6}, Uhn-Soo Cho⁷

Affiliations

¹ Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA.
² Department of Pathology, University of Michigan, Ann Arbor, Michigan, 48109, USA.
³ Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA.
⁴ Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, 48109, USA.
⁵ Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA. yalid@med.umich.edu.
⁶ Department of Pathology, University of Michigan, Ann Arbor, Michigan, 48109, USA. yalid@med.umich.edu.
⁷ Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA. uhnsoo@med.umich.edu.

Abstract

Mixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome core particles (NCPs) remain unclear. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the NCP-bound human MLL1 core complex. We show that the MLL1 core complex anchors to the NCP via the conserved RbBP5 and ASH2L, which interact extensively with nucleosomal DNA and the surface close to the N-terminal tail of histone H4. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1^SET domain at the nucleosome dyad, thereby facilitating symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Nucleus / metabolism
Cryoelectron Microscopy / methods*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Histone-Lysine N-Methyltransferase / ultrastructure
Histones / metabolism*
Humans
Lysine / metabolism
Methylation
Mutation
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism*
Myeloid-Lymphoid Leukemia Protein / ultrastructure
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Nucleosomes / metabolism*
Nucleosomes / ultrastructure
Protein Binding
Transcription Factors / genetics
Transcription Factors / metabolism
Xenopus laevis

Substances

ASH2L protein, human
DNA-Binding Proteins
Histones
KMT2A protein, human
Nuclear Proteins
Nucleosomes
RBBP5 protein, human
Transcription Factors
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding