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

Autor: Arvindekar S; National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India., Jackman MJ; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia., Low JKK; School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia., Landsberg MJ; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia., Mackay JP; School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia., Viswanath S; National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2022 Sep; Vol. 31 (9), pp. e4387.
DOI: 10.1002/pro.4387
Abstrakt: 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, MTA1 N -HDAC1-MBD3 GATAD2CC , and MTA1-HDAC1-RBBP4-MBD3-GATAD2A [nucleosome deacetylase (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.
(© 2022 The Protein Society.)
Databáze: MEDLINE
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