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Reference: Arnold KM, et al. (2011) Processing Mechanism and Substrate Selectivity of the Core NuA4 Histone Acetyltransferase Complex. Biochemistry 50(5):727-37

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Abstract

Esa1, an essential MYST histone acetyltransferase found in the yeast piccolo NuA4 complex (picNuA4), is responsible for genome-wide histone H4 and histone H2A acetylation. picNuA4 uniquely catalyzes the rapid tetra-acetylation of nucleosomal H4, though the molecular determinants driving picNuA4 efficiency and specificity have not been defined. Here, we show through rapid substrate-trapping experiments that picNuA4 utilizes a non-processive mechanism, where picNuA4 dissociates from substrate after each acetylation event. Quantitative mass spectral analyses indicate that picNuA4 randomly acetylates free and nucleosomal H4, with a small preference for lysines 5, 8, and 12 over 16. Using a series of 24 histone mutants of H4 and H2A, we investigated the parameters affecting catalytic efficiency. Most strikingly, removal of lysine residues did not substantially affect the ability of picNuA4 to acetylate remaining sites, and insertion of an additional lysine into the H4 tail led to rapid quintuple-acetylation. Conversion of the native H2A tail to an H4-like sequence resulted in enhanced multi-site acetylation. Collectively, the results suggest picNuA4's site selectivity is dictated by accessibility on the nucleosome surface, the relative proximity from the histone fold domain, and a preference for intervening glycine residues with a minimal (n + 2) spacing between lysines. Functionally distinct from other HAT families, the proposed model for picNuA4 represents a unique mechanism of substrate recognition and multisite acetylation.

Reference Type
Journal Article
Authors
Arnold KM, Lee S, Denu JM
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