Histone chaperone exploits intrinsic disorder to switch acetylation specificity

Lukas Lercher,John Kirkpatrick,Luca Codutti,Nataliya Danilenko,Frank Gabel,Teresa Carlomagno

doi:10.1038/s41467-019-11410-7

Abstract

Histones, the principal protein components of chromatin, contain long disordered sequences, which are extensively post-translationally modified. Although histone chaperones are known to control both the activity and specificity of histone-modifying enzymes, the mechanisms promoting modification of highly disordered substrates, such as lysine-acetylation within the N-terminal tail of histone H3, are not understood. Here, to understand how histone chaperones Asf1 and Vps75 together promote H3 K9-acetylation, we establish the solution structural model of the acetyltransferase Rtt109 in complex with Asf1 and Vps75 and the histone dimer H3:H4. We show that Vps75 promotes K9-acetylation by engaging the H3 N-terminal tail in fuzzy electrostatic interactions with its disordered C-terminal domain, thereby confining the H3 tail to a wide central cavity faced by the Rtt109 active site. These fuzzy interactions between disordered domains achieve localization of lysine residues in the H3 tail to the catalytic site with minimal loss of entropy, and may represent a common mechanism of enzymatic reactions involving highly disordered substrates.

Highlights

Histones, the principal protein components of chromatin, contain long disordered sequences, which are extensively post-translationally modified
The mechanisms by which chaperones promote chemical modification of structured regions have been described in many systems and include binding to both enzyme and substrate, optimization of interaction interfaces and substrate presentation
We demonstrate that Vps[75] and Asf[1] act in concert to promote acetylation of H3-K9, located in the long unstructured H3 tail, by a two-fold mechanism that minimizes the inevitable entropic costs associated with enzymatic modification of sites within intrinsically disordered regions (Fig. 6)

Summary

Introduction

The principal protein components of chromatin, contain long disordered sequences, which are extensively post-translationally modified. We show that Vps[75] promotes K9-acetylation by engaging the H3 Nterminal tail in fuzzy electrostatic interactions with its disordered C-terminal domain, thereby confining the H3 tail to a wide central cavity faced by the Rtt[109] active site These fuzzy interactions between disordered domains achieve localization of lysine residues in the H3 tail to the catalytic site with minimal loss of entropy, and may represent a common mechanism of enzymatic reactions involving highly disordered substrates. Rtt[109] shows very little activity on isolated histones, but efficiently acetylates H3:H4 dimers associated with the histone chaperones Asf[1] (anti-silencing function protein 1) and Vps[75] (vacuolar protein sorting-associated protein 75)[10,11,17,18]. H3-K56 is found to extend into the Rtt[109] catalytic site, but there is no well-defined electron-density for the H3 N-

Methods

Results

Conclusion