title: Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.
abstract: Histone deacetylases (HDACs) regulate chromatin status and gene expression, and their inhibition is of significant therapeutic interest. To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and inhibitor-free structures of the histone deacetylase-4 catalytic domain (HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity toward acetylated lysines. The structures presented, coupled with activity data, provide the molecular basis for the intrinsically low enzymatic activity of class IIa HDACs toward acetylated lysines and reveal active site features that may guide the design of class-specific inhibitors. In addition, these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes. Importantly, either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex. Together, these data suggest a key role of the structural zinc-binding domain in the regulation of class IIa HDAC functions.
authors.affiliation: Istituto di Ricerche di Biologia Molecolare P. Angeletti, Merck Research Laboratories, Via Pontina Km 30.600, 00040 Pomezia (Roma), Italy.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bottomley
authors.forename: Paola
authors.initials: P
authors.lastname: Lo Surdo
authors.forename: Paolo
authors.initials: P
authors.lastname: Di Giovine
authors.forename: Agostino
authors.initials: A
authors.lastname: Cirillo
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrigno
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.forename: Petra
authors.initials: P
authors.lastname: Neddermann
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfí
mesh_terms: D000107:Acetylation; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D018360:Crystallography, X-Ray; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002843:Chromatin; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D015032:Zinc