Controlled assembly and disassembly of multi-protein complexes is central to cellular signaling. Proteins of the widespread and functionally diverse HORMA family nucleate assembly of signaling complexes by binding short peptide motifs through a distinctive safety-belt mechanism. HORMA proteins are now understood as key signaling proteins across kingdoms, serving as infection sensors in a bacterial immune system and playing central roles in eukaryotic cell cycle, genome stability, sexual reproduction, and cellular homeostasis pathways. Here, we describe how HORMA proteins’ unique ability to adopt multiple conformational states underlies their functions in these diverse contexts. We also outline how a dedicated AAA+ ATPase regulator, Pch2/TRIP13, manipulates HORMA proteins’ conformational states to activate or inactivate signaling in different cellular contexts. The emergence of Pch2/TRIP13 as a lynchpin for HORMA protein action in multiple genome-maintenance pathways accounts for its frequent misregulation in human cancers and highlights TRIP13 as a novel therapeutic target.

中文翻译：

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HORMA 结构域蛋白信号传导的进化动力学和分子机制

多蛋白复合物的受控组装和分解是细胞信号传导的核心。广泛且功能多样的 HORMA 家族的蛋白质通过独特的安全带机制结合短肽基序，使信号复合物的组装成核。 HORMA 蛋白现在被认为是跨界的关键信号蛋白，充当细菌免疫系统中的感染传感器，并在真核细胞周期、基因组稳定性、有性生殖和细胞稳态途径中发挥核心作用。在这里，我们描述了 HORMA 蛋白采用多种构象状态的独特能力如何成为其在这些不同背景下发挥功能的基础。我们还概述了专用的 AAA+ ATP 酶调节剂 Pch2/TRIP13 如何操纵 HORMA 蛋白的构象状态以激活或失活不同细胞环境中的信号传导。 Pch2/TRIP13 作为 HORMA 蛋白在多个基因组维持途径中发挥作用的关键，其出现解释了其在人类癌症中频繁发生的错误调节，并凸显了 TRIP13 作为一种新的治疗靶点。