与 SET1 (COMPASS) 相关的复合物是一种组蛋白 H3K4 三甲基转移酶，受多个调节亚基（包括 CXXC 锌指蛋白 1 (Cfp1)）控制。先前的研究建立了控制 Cfp1 酵母同源物 (Spp1) 的 PHD 结构域识别 H3K4me3 的结构基础。然而，后生动物 Cfp1PHD 缺乏对 Spp1 中 H3K4me3 稳定重要的结构元件，这表明在后生动物中，Cfp1PHD 结构域与 H3K4me3 的结合不同。与 H3K4me3 复合的 Cfp1PHD 结构显示出独特的特征，例如第一个锌原子的非规范配位和迫使 Cfp1PHD N 末端重新定向的二硫键，从而导致非典型的 H3K4me3 结合口袋。这种配置最大限度地减少了 Cfp1PHD 对对其他 PHD 结构域的组蛋白结合功能很重要的规范残基的依赖。 Cfp1PHD 中的癌症相关突变会损害 H3K4me3 结合，这意味着对表观遗传信号传导存在潜在影响。我们的工作强调了 PHD 组蛋白结合模式的潜在多样化以及癌症突变对 Cfp1 功能的影响。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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 Cfp1PHD lacks structural elements important for H3K4me3 stabilization in Spp1, suggesting that in metazoans, Cfp1PHD domain binds H3K4me3 differently. The structure of Cfp1PHD 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 Cfp1PHD N-terminus, thereby leading to an atypical H3K4me3 binding pocket. This configuration minimizes Cfp1PHD reliance on canonical residues important for histone binding functions of other PHD domains. Cancer-related mutations in Cfp1PHD 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.Copyright © 2024 Elsevier Inc. All rights reserved.