The double PHD finger domain of MOZ/MYST3 induces α-helical structure of the histone H3 tail to facilitate acetylation and methylation sampling and modification

Ingrid Dreveny,Joel Fulton,Sian E Deeves,David M Heery,Amit Bhattacharya,Baigong Yue,Hilary M Collins,Marie Messmer

doi:10.1093/nar/gkt931

Abstract

Histone tail modifications control many nuclear processes by dictating the dynamic exchange of regulatory proteins on chromatin. Here we report novel insights into histone H3 tail structure in complex with the double PHD finger (DPF) of the lysine acetyltransferase MOZ/MYST3/KAT6A. In addition to sampling H3 and H4 modification status, we show that the DPF cooperates with the MYST domain to promote H3K9 and H3K14 acetylation, although not if H3K4 is trimethylated. Four crystal structures of an extended DPF alone and in complex with unmodified or acetylated forms of the H3 tail reveal the molecular basis of crosstalk between H3K4me3 and H3K14ac. We show for the first time that MOZ DPF induces α-helical conformation of H3K4-T11, revealing a unique mode of H3 recognition. The helical structure facilitates sampling of H3K4 methylation status, and proffers H3K9 and other residues for modification. Additionally, we show that a conserved double glycine hinge flanking the H3 tail helix is required for a conformational change enabling docking of H3K14ac with the DPF. In summary, our data provide the first observations of extensive helical structure in a histone tail, revealing the inherent ability of the H3 tail to adopt alternate conformations in complex with chromatin regulators.

Highlights

Histone N-terminal tails are subject to multiple posttranslational modifications (PTMs) that can modify chromatin structure and act as signals to recruit, evict or repel chromatin regulators
We report a series of four crystal structures of an extended monocytic leukaemia zinc finger protein (MOZ) double PHD finger (DPF) domain alone and in complex with the H3 N-terminal tail, including unmodified, H3K9ac and H3K14ac forms providing detailed novel insights into the consequences of PTM on H3 tail structure in complex with a DPF
Peptide surrogates demonstrated that this interaction is mediated by the H3 N-terminal tail, as MOZ DPF showed a robust interaction with H3 [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21] (Figure 1B), but not H3 [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44] (Supplementary Figure S1C)

Summary

Introduction

Histone N-terminal tails are subject to multiple posttranslational modifications (PTMs) that can modify chromatin structure and act as signals to recruit, evict or repel chromatin regulators. Dynamic changes in histone PTMs reflect the expression status of genes and their regulatory regions, the ability of chromatin regulators to recognize combinatorial heterotypic PTMs in their histone substrates is essential to their function Supporting evidence for this model comes from structural studies of histone tail recognition by the tandem bromodomains of bromodomain, testis specific (BRDT) [3], the plant homeodomain (PHD finger) and double tudor domains of ubiquitin-like with PHD finger and RING domains 1 (UHRF1) [4] and the dual PHD/Bromo domains of bromodomain PHD finger transcription factor (BPTF) [5]. A systematic study of the interactions of bromodomains with acetylated histone peptides suggests that multivalent recognition of PTMs is an important and widespread function of chromatin readers [6] This sampling functionality is likely to underpin crosstalk between different histone PTM signals, facilitating recruitment and dismissal of chromatin regulators to drive genomic processes. Understanding these processes at the molecular level will be essential for devising new therapeutic interventions in human diseases such as cancer, in which chromatin functions are disrupted

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