美国哈佛大学Brian B. Liau研究小组宣布他们的最新研究揭示了UM171和KBTBD4新形态癌突变的趋同机制。相关论文于2025年2月12日发表在《自然》杂志上。

在这里，研究小组发现KBTBD4突变通过将HDAC1/2作为突变底物受体的直接靶点来促进CoREST降解。利用深度突变扫描，该课题组绘制了KBTBD4癌症热点的突变图，揭示了插入和替换促进功能获得的不同偏好，以及参与热点相互作用的关键残基。冷冻电镜分析了两个不同的结合LSD1-HDAC1-CoREST的KBTBD4癌症突变体，发现KBTBD4同型二聚体不对称地结合HDAC1和两个KELCH-repeat β-螺旋桨结构域。髓母细胞瘤突变稳定了HDAC1和KBTBD4 β-螺旋桨之间的界面，将一个庞大的侧链插入HDAC1活性位点口袋中。

他们的结构和突变分析揭示了热点E3 -新衬底界面如何进行化学调制。首先，该研究团队揭示了功能获得性E3突变和分子胶降解剂UM171之间基于形状互补的趋同机制。其次，课题组证明HDAC1/2抑制剂可以阻断突变体KBTBD4-HDAC1界面和KBTBD4突变体髓母细胞瘤细胞的增殖。总之，他们的工作揭示了癌症突变驱动的新形态蛋白-蛋白相互作用的结构和机制基础。

据悉，癌症突变可以产生新形态的蛋白质相互作用，从而驱动异常功能。作为CULLIN3-RING E3泛素连接酶复合物的底物受体，KBTBD4在髓母细胞瘤（儿童中最常见的胚胎性脑肿瘤）中反复发生突变。这些突变使KBTBD4获得功能，从而诱导转录共抑制因子CoREST5的异常降解。然而，其机制仍未得到解决。

附：英文原文

Title: Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations

Author: Xie, Xiaowen, Zhang, Olivia, Yeo, Megan J. R., Lee, Ceejay, Tao, Ran, Harry, Stefan A., Payne, N. Connor, Nam, Eunju, Paul, Leena, Li, Yiran, Kwok, Hui Si, Jiang, Hanjie, Mao, Haibin, Hadley, Jennifer L., Lin, Hong, Batts, Melissa, Gosavi, Pallavi M., DAngiolella, Vincenzo, Cole, Philip A., Mazitschek, Ralph, Northcott, Paul A., Zheng, Ning, Liau, Brian B.

Issue&Volume: 2025-02-12

Abstract: Cancer mutations can create neomorphic protein–protein interactions to drive aberrant function1,2. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma3, the most common embryonal brain tumour in children4. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST5. However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1–HDAC1–CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3–neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4–HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein–protein interactions.

DOI: 10.1038/s41586-024-08533-3

Source: https://www.nature.com/articles/s41586-024-08533-3