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The MLL1 trimeric catalytic complex is a dynamic conformational ensemble stabilized by multiple weak interactions

  1. Author:
    Kaustov, Lilia
    Lemak, Alexander
    Wu, Hong
    Faini, Marco
    Fan,Lixin
    Fang, Xianyang
    Zeng, Hong
    Duan, Shili
    Allali-Hassani, Abdellah
    Li, Fengling
    Wei, Yong
    Vedadi, Masoud
    Aebersold, Ruedi
    Wang,Yun-Xing
    Houliston, Scott
    Arrowsmith, Cheryl H

  2. Author Address

    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, ON M5G 2M9, Canada., Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada., Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada., Department of Biology, Institute of Molecular Systems Biology, ETH Z 252;rich, 8093 Z 252;rich, Switzerland., The Small-Angel X-ray Scattering Core Facility, Center for Cancer Research of National Cancer Institute, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc. Frederick, MD 21702, USA., Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada., Faculty of Science, University of Z 252;rich, 8057 Z 252;rich, Switzerland.,
    1. Year: 2019
    2. Date: SEP 26
    3. Epub Date: 2019 08 10
  2. Journal: Nucleic acids research
    1. 47
    2. 17
    3. Pages: 9433-9447
  4. Type of Article: Article
  5. ISSN: 0305-1048
  1. Abstract:

    Histone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. The catalytic activity of this family is dependent on interactions with additional conserved proteins, but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering, cross-linking mass spectrometry, nuclear magnetic resonance spectroscopy and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 ß-propeller domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites. © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.

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External Sources

  1. View Full Text
  2. DOI: 10.1093/nar/gkz697
  3. PMID: 31400120
  4. View record in Web of Science®
  5. WOS: 000490579200042
  6. PII : 5545732

Library Notes

  1. Fiscal Year: FY2018-2019
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