期刊
CELL REPORTS
卷 17, 期 10, 页码 2724-2737出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.11.014
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资金
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) (UL-TRA-DD) [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust [092809/Z/10/Z, 090532/Z/09/Z]
- Wellcome Career Development Fellowship [095751/Z/11/Z]
- Ludwig Cancer Research
- Medical Research Council [MR/N010051/1]
- Uehara Memorial Foundation Fellowship [201330102]
- Government of Canada through Genome Canada [OGI-088, OGI-097]
- Government of Canada through the Ontario Genomics Institute [OGI-088, OGI-097]
- Canadian Institutes of Health Research [FDN 143301]
- CIHR
- TD Bank Health Research Fellowship at the Lunenfeld-Tanenbaum Research Institute
- NIH [GM068088]
- National Institute of General Medical Sciences Division of Training, Workforce Development, and Diversity under the Institutional Research and Academic Career Development Award [K12-GM000678]
- SGC, a registered charity [1097737]
- Medical Research Council [MR/N010051/1] Funding Source: researchfish
- MRC [MR/N010051/1] Funding Source: UKRI
Elucidation of interactions involving DNA and histone post-translational-modifications (PTMs) is essential for providing insights into complex biological functions. Reader assemblies connected by flexible linkages facilitate avidity and increase affinity; however, little is known about the contribution to the recognition process of multiple PTMs because of rigidity in the absence of conformational flexibility. Here, we resolve the crystal structure of the triple reader module (PHD-BRD-PWWP) of ZMYND8, which forms a stable unit capable of simultaneously recognizing multiple histone PTMs while presenting a charged platform for association with DNA. Single domain disruptions destroy the functional network of interactions initiated by ZMYND8, impairing recruitment to sites of DNA damage. Our data establish a proof of principle that rigidity can be compensated by concomitant DNA and histone PTM interactions, maintaining multivalent engagement of transient chromatin states. Thus, our findings demonstrate an important role for rigid multivalent reader modules in nucleosome binding and chromatin function.
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