哺乳动物 HORMA 结构域蛋白 1 (HORMAD1) 调节许多癌症中的 DNA 错配修复和同源重组 (HR) 修复。在这里，我们发现人类 HORMAD1 的结构采用自闭合构象，并显示出分子内 HORMA 结构域闭合基序相互作用模式。结构和生化数据表明，HORMAD2 和 MCM9 的肽基序与 HORMAD1 的相互作用模式与 HORMAD1 自身的闭合基序高度相似。来自 HORMAD1 不同结合伴侣的肽基序共享保守的 Ser-Glu-Pro 序列。此外，结构比较揭示了含有 HORMA 的蛋白质之间 HORMA 肽基序相互作用模式的多样性。最后，基于细胞的检测表明，这种 HORMA 闭合基序相互作用模式有助于 DNA 错配修复，并且是 HORMAD1 依赖性 HR 修复所必需的。总之，我们的结果为含 HORMA 结构域的蛋白质家族的共同主题和功能可塑性提供了结构和生化见解，并揭示了 HORMAD1 的通用调节机制。版权所有 © 2023 Elsevier Ltd。保留所有权利。

The mammalian HORMA domain-containing protein 1 (HORMAD1) regulates DNA mismatch repair and homologous recombination (HR) repair in many cancers. Here, we show that the structure of human HORMAD1 adopts a self-closed conformation and displays an intra-molecular HORMA domain-closure motif interaction mode. Structural and biochemical data suggest that the interaction modes of the peptide motifs from HORMAD2 and MCM9 with HORMAD1 are highly similar to that of HORMAD1 own closure motif. The peptide motifs from diverse binding partners of HORMAD1 share a conserved Ser-Glu-Pro sequence. Additionally, structural comparison unveiled the HORMA-peptide motif interaction mode diversity among HORMA-containing proteins. Finally, cell-based assays revealed that this HORMA-closure motif interaction pattern contributes to DNA mismatch repair and is required for HORMAD1-dependent HR repair. Together, our results provide structural and biochemical insights into the common theme and functional plasticity of the HORMA domain-containing protein family, and also reveal a universal regulation mechanism for HORMAD1.Copyright © 2023 Elsevier Ltd. All rights reserved.