Structural insights into an atypical histone binding mechanism by a PHD finger

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-07-18 DOI:10.1016/j.str.2024.06.017

引用次数: 0

Abstract

Complex associating with SET1 (COMPASS) is a histone H3K4 tri-methyltransferase controlled by several regulatory subunits including CXXC zinc finger protein 1 (Cfp1). Prior studies established the structural underpinnings controlling H3K4me3 recognition by the PHD domain of Cfp1’s yeast homolog (Spp1). However, metazoans Cfp1^PHD lacks structural elements important for H3K4me3 stabilization in Spp1, suggesting that in metazoans, Cfp1^PHD domain binds H3K4me3 differently. The structure of Cfp1^PHD in complex with H3K4me3 shows unique features such as non-canonical coordination of the first zinc atom and a disulfide bond forcing the reorientation of Cfp1^PHD N-terminus, thereby leading to an atypical H3K4me3 binding pocket. This configuration minimizes Cfp1^PHD reliance on canonical residues important for histone binding functions of other PHD domains. Cancer-related mutations in Cfp1^PHD impair H3K4me3 binding, implying a potential impact on epigenetic signaling. Our work highlights a potential diversification of PHD histone binding modes and the impact of cancer mutations on Cfp1 functions.

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从结构上揭示 PHD 指的非典型组蛋白结合机制

与 SET1 有关的复合体（COMPASS）是一种组蛋白 H3K4 三甲基转移酶，由包括 CXXC 锌指蛋白 1（Cfp1）在内的多个调控亚基控制。先前的研究确定了 Cfp1 的酵母同源物（Spp1）的 PHD 结构域控制 H3K4me3 识别的结构基础。然而，元古动物的 Cfp1PHD 缺乏对 Spp1 中 H3K4me3 稳定起重要作用的结构元素，这表明在元古动物中，Cfp1PHD 结构域与 H3K4me3 的结合方式不同。Cfp1PHD 与 H3K4me3 复合物的结构显示了一些独特的特征，如第一个锌原子的非规范配位和二硫键迫使 Cfp1PHD N 端重新定向，从而形成了一个非典型的 H3K4me3 结合口袋。这种构型最大程度地减少了 Cfp1PHD 对其他 PHD 结构域组蛋白结合功能所需的典型残基的依赖。Cfp1PHD 中与癌症相关的突变会影响 H3K4me3 的结合，这意味着它可能会对表观遗传信号转导产生影响。我们的研究突显了 PHD 组蛋白结合模式的潜在多样性以及癌症突变对 Cfp1 功能的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.