title: Structural aspects of HDAC8 mechanism and dysfunction in Cornelia de Lange syndrome spectrum disorders.
abstract: Cornelia de Lange Syndrome (CdLS) encompasses a broad spectrum of phenotypes characterized by distinctive craniofacial abnormalities, limb malformations, growth retardation, and intellectual disability. CdLS spectrum disorders are referred to as cohesinopathies, with ∼70% of patients having a mutation in a gene encoding a core cohesin protein (SMC1A, SMC3, or RAD21) or a cohesin regulatory protein (NIPBL or HDAC8). Notably, the regulatory function of HDAC8 in cohesin biology has only recently been discovered. This Zn2+-dependent hydrolase catalyzes the deacetylation of SMC3, a necessary step for cohesin recycling during the cell cycle. To date, 23 different missense mutants in the gene encoding HDAC8 have been identified in children with developmental features that overlap those of CdLS. Enzymological, biophysical, and structural studies of CdLS HDAC8 protein mutants have yielded critical insight on compromised catalysis in vitro. Most CdLS HDAC8 mutations trigger structural changes that directly or indirectly impact substrate binding and catalysis. Additionally, several mutations significantly compromise protein thermostability. Intriguingly, catalytic activity in many HDAC8 mutants can be partially or fully restored by an N-acylthiourea activator, suggesting a plausible strategy for the chemical rescue of compromised HDAC8 catalysis in vivo.
authors: Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Pennsylvania, 19104. deardorff@email.chop.edu.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104. deardorff@email.chop.edu.
authors: Matthew A
authors: MA
authors: Deardorff
authors: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104-6323.
authors: Nicholas J
authors: NJ
authors: Porter
authors: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104-6323. chris@sas.upenn.edu.
authors: David W
authors: DW
authors: Christianson
mesh_terms: D000215:Acylation; D000818:Animals; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003635:De Lange Syndrome / Q000201:enzymology / Q000235:genetics; D004795:Enzyme Stability; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D006655:Histone Deacetylases; D012097:Repressor Proteins; D013890:Thiourea; D000097722:Cohesins; C409470:HDAC8 protein, human
keywords: birth defect; human genetics; lysine deacetylase; protein crystallography; zinc enzyme