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Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders

Osko, Jeremy D. and Porter, Nicholas J. and Decroos, Christophe and Lee, Matthew S. and Watson, Paris R. and Raible, Sarah E. and Krantz, Ian D. and Deardorff, Matthew A. and Christianson, David W. (2021) Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders. Journal of Structural Biology, 213 (1). Art. No. 107681. ISSN 1047-8477. PMCID PMC7981260. https://resolver.caltech.edu/CaltechAUTHORS:20210414-134541385

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Abstract

Cornelia de Lange Syndrome (CdLS) and associated spectrum disorders are characterized by one or more congenital anomalies including distinctive facial features, upper limb abnormalities, intellectual disability, and other symptoms. The molecular genetic basis of CdLS is linked to defects in cohesin, a protein complex that functions in sister chromatid cohesion, chromatin organization, and transcriptional regulation. Histone deacetylase 8 (HDAC8) plays an important role in cohesin function by catalyzing the deacetylation of SMC3, which is required for efficient recycling of the cohesin complex. Missense mutations in HDAC8 have been identified in children diagnosed with CdLS spectrum disorders, and here we outline structure-function relationships for four of these mutations. Specifically, we report the 1.50 Å-resolution structure of the I45T HDAC8–suberoylanilide hydroxamic acid complex, the 1.84 Å-resolution structure of E66D/Y306F HDAC8 complexed with a peptide assay substrate, and the 2.40 Å-resolution structure of G320R HDAC8 complexed with the inhibitor M344. Additionally, we present a computationally generated model of D176G HDAC8. These structures illuminate new structure-function relationships for HDAC8 and highlight the importance of long-range interactions in the protein scaffold that can influence catalytic function.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.jsb.2020.107681DOIArticle
ORCID:
AuthorORCID
Osko, Jeremy D.0000-0001-8595-4759
Porter, Nicholas J.0000-0002-9803-5310
Watson, Paris R.0000-0002-6990-525X
Krantz, Ian D.0000-0003-2442-1128
Additional Information:© 2020 Elsevier Inc. Received 10 November 2020, Revised 5 December 2020, Accepted 8 December 2020, Available online 11 December 2020. We thank the U.S. National Institutes of Health (NIH) for grant GM49758 in support of this research. This research is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences of the NIH (P30 GM124165). The Eiger 16 M detector on the 24-ID-E beam line is funded by an NIH-ORIP HEI grant (S10OD021527). This research utilized resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Additionally, this research utilized the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, which is supported by the DOE Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institute of General Medical Sciences of the NIH (P41GM103393). CRediT authorship contribution statement: Jeremy D. Osko: Methodology, Investigation, Formal analysis, Writing - original draft, Visualization. Nicholas J. Porter: Methodology, Investigation, Formal analysis. Christophe Decroos: Methodology, Investigation, Formal analysis. Matthew S. Lee: Methodology, Investigation, Formal analysis. Paris R. Watson: Methodology, Investigation, Formal analysis. Sarah E. Raible: Methodology, Investigation, Formal analysis. Ian D. Krantz: Methodology, Investigation, Formal analysis. Matthew A. Deardorff: Conceptualization, Methodology, Investigation, Formal analysis, Project administration. David W. Christianson: Conceptualization, Methodology, Investigation, Formal analysis, Project administration. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funders:
Funding AgencyGrant Number
NIHGM49758
NIHP30 GM124165
NIHS10OD021527
Department of Energy (DOE)DE-AC02-06CH11357
Department of Energy (DOE)DE-AC02-76SF00515
NIHP41GM103393
Subject Keywords:X-ray crystallography; Zinc enzyme; Cohesin; Birth defect
Issue or Number:1
PubMed Central ID:PMC7981260
Record Number:CaltechAUTHORS:20210414-134541385
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210414-134541385
Official Citation:Jeremy D. Osko, Nicholas J. Porter, Christophe Decroos, Matthew S. Lee, Paris R. Watson, Sarah E. Raible, Ian D. Krantz, Matthew A. Deardorff, David W. Christianson, Structural analysis of histone deacetylase 8 mutants associated with Cornelia de Lange Syndrome spectrum disorders, Journal of Structural Biology, Volume 213, Issue 1, 2021, 107681, ISSN 1047-8477, https://doi.org/10.1016/j.jsb.2020.107681.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108733
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Apr 2021 22:02
Last Modified:19 Apr 2021 17:09

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