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PreprintCited by 23Genomics and Chromatin DynamicsChromatin Remodeling and CancerProtein Structure and Dynamics

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Molecular architecture of nucleosome remodeling and deacetylase sub-complexes by integrative structure determination

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Arvindekar, Shreyas, Jackman, Matthew J., Low, Jason K.K., Landsberg, Michael J., Mackay, Joel P., Viswanath, Shruthi·2021·Protein Science
DOI 10.1101/2021.11.25.469965PMC PMC9413472

Preprint — published as 10.1002/pro.4387 · Paper page

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Abstract

The Nucleosome Remodeling and Deacetylase (NuRD) complex is a chromatin-modifying assembly that regulates gene expression and DNA damage repair. Despite its importance, limited structural information describing the complete NuRD complex is available and a detailed understanding of its mechanism is therefore lacking. Drawing on information from SEC-MALLS, DIA-MS, XLMS, negative-stain EM, X-ray crystallography, NMR spectroscopy, secondary structure predictions and homology models, we applied Bayesian integrative structure determination to investigate the molecular architecture of three NuRD sub-complexes: MTA1-HDAC1-RBBP4 (MHR), MTA1 N -HDAC1-MBD3 GATAD2CC (MHM), and MTA1-HDAC1-RBBP4-MBD3-GATAD2A (NuDe). The integrative structures were corroborated by examining independent crosslinks, cryo-EM maps, biochemical assays, known cancer-associated mutations, and structure predictions from AlphaFold. The robustness of the models was assessed by jack-knifing. Localization of the full-length MBD3, which connects the deacetylase and chromatin remodeling modules in NuRD, has not previously been possible; our models indicate two different locations for MBD3, suggesting a mechanism by which MBD3 in the presence of GATAD2A asymmetrically bridges the two modules in NuRD. Further, our models uncovered three previously unrecognized subunit interfaces in NuDe: HDAC1 C -MTA1 BAH , MTA1 BAH -MBD3 MBD , and HDAC1 60-100 -MBD3 MBD . Our approach also allowed us to localize regions of unknown structure, such as HDAC1 C and MBD3 IDR , thereby resulting in the most complete and robustly cross-validated structural characterization of these NuRD sub-complexes so far.

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Metadata

Authors
Arvindekar, S., Jackman, M. J., Low, J. K. K., Landsberg, M. J., Mackay, J. P., & Viswanath, S.
Affiliations
  • Tata Institute of Fundamental Research (IN)
  • The University of Queensland (AU)
  • The University of Sydney (AU)
Corresponding author
  • Landsberg, Michael J.
  • Mackay, Joel P.
  • Viswanath, Shruthi
ORCID
Venue
Protein Science
Publisher
openRxiv
Published
2021-11-25
Volume
31
Issue
9
Pages
e4387-e4387
ISSN
0961-8368 (ISSN-L)
DOI
10.1101/2021.11.25.469965
PMC
PMC9413472
OpenAlex
W4293109432
Cited by
23
References
1
Citations by year
2026: 7 · 2025: 5 · 2024: 7 · 2023: 2 · 2022: 2
FWCI
1.31
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Protein Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Tata Institute of Fundamental Research (RTI4006)
  • Department of Science and Technology, Ministry of Science and Technology, India
  • Department of Atomic Energy, Government of India (RTI 4006)
  • National Institutes of Health (APP1126357, NIH-R01, APP1063301, APP1058916, APP1012161, RR001081, NIH P41 RR001081)
  • University of California, San Francisco (R01-GM129325)
  • Medical Research Council
  • National Health and Medical Research Council (1012161, 1058916, 1063301, 1126357)
  • Science and Engineering Research Board (SPG/2020/000475)
  • National Institute of General Medical Sciences (R01GM129325)
  • National Institute of Allergy and Infectious Diseases (NIH P41)
  • National Center for Research Resources (P41RR001081)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
NuRD complex, nucleosome remodeling, histone deacetylase, MTA1, HDAC1, RBBP4, MBD3, GATAD2A, protein complex structure, subunit interface, chromatin remodeling, gene expression regulation
MeSH terms
Bayes Theorem, Histone Deacetylases, Nucleosomes, Chromatin Assembly and Disassembly, Mi-2 Nucleosome Remodeling and Deacetylase Complex

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