The internal interaction in RBBP5 regulates assembly and activity of MLL1 methyltransferase complex

Jianming Han; Tingting Li; Yanjing Li; Muchun Li; Xiaoman Wang; Chao Peng; Chen Su; Na Li; Yiwen Li; Ying Xu; Yong Chen

doi:10.1093/nar/gkz819

The internal interaction in RBBP5 regulates assembly and activity of MLL1 methyltransferase complex

Nucleic Acids Res. 2019 Nov 4;47(19):10426-10438. doi: 10.1093/nar/gkz819.

Authors

Jianming Han¹, Tingting Li¹, Yanjing Li¹, Muchun Li², Xiaoman Wang¹, Chao Peng^{3

4}, Chen Su^{3

4}, Na Li³, Yiwen Li³, Ying Xu¹, Yong Chen^{1

2

4}

Affiliations

¹ State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.
² School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China.
³ National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai 201210, China.
⁴ Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.

Abstract

The Mixed Lineage Leukemia protein 1 (MLL1) plays an essential role in the maintenance of the histone H3 lysine 4 (H3K4) methylation status for gene expression during differentiation and development. The methyltransferase activity of MLL1 is regulated by three conserved core subunits, WDR5, RBBP5 and ASH2L. Here, we determined the structure of human RBBP5 and demonstrated its role in the assembly and regulation of the MLL1 complex. We identified an internal interaction between the WD40 propeller and the C-terminal distal region in RBBP5, which assisted the maintenance of the compact conformation of the MLL1 complex. We also discovered a vertebrate-specific motif in the C-terminal distal region of RBBP5 that contributed to nucleosome recognition and methylation of nucleosomes by the MLL1 complex. Our results provide new insights into functional conservation and evolutionary plasticity of the scaffold protein RBBP5 in the regulation of KMT2-family methyltransferase complexes.

Publication types

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

MeSH terms

Cell Differentiation / genetics
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / genetics
DNA-Binding Proteins / ultrastructure*
Histone-Lysine N-Methyltransferase / chemistry
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / ultrastructure*
Histones / genetics
Humans
Intracellular Signaling Peptides and Proteins
Molecular Conformation
Multiprotein Complexes / chemistry
Multiprotein Complexes / genetics
Multiprotein Complexes / ultrastructure*
Myeloid-Lymphoid Leukemia Protein / chemistry
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / ultrastructure*
Nuclear Proteins / genetics
Protein Binding / genetics
Protein Conformation
Protein Interaction Domains and Motifs / genetics
Transcription Factors / chemistry
Transcription Factors / genetics*

Substances

ASH2L protein, human
DNA-Binding Proteins
Histones
Intracellular Signaling Peptides and Proteins
KMT2A protein, human
Multiprotein Complexes
Nuclear Proteins
RBBP5 protein, human
Transcription Factors
WDR5 protein, human
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase