Scaffolding Activities of Pseudodeacetylase HDAC7.

Abstract

Histone deacetylase (HDAC) enzymes remove acetyl groups from acetyllysine-containing proteins, including nucleosomal histones to control gene expression. Beyond fundamental cell biology, HDAC activity is linked to various cancers, with many HDAC inhibitors developed as anticancer therapeutics. Among the 11 metal-dependent HDAC proteins, the four class IIa isoforms (HDAC4, 5, 7, and 9) are "pseudodeacetylases" without measurable enzymatic activity due to mutation of a catalytic tyrosine. Deacetylase-related activities of class IIa HDAC proteins are attributed to scaffolding functions, where recruitment of an active HDAC isoform leads to bound substrate deacetylation. Scaffolding of class IIa proteins beyond simple recruitment of an active HDAC is only starting to emerge. This review explores the various scaffolding roles of HDAC7, including recently reported acetylation-mediated reversible scaffolding, which is a form of acetyllysine-binding reader function. Studying the functional roles of HDAC7 will provide molecular insight into normal and pathological conditions, which could facilitate drug design.