Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Haihe Laboratory of Cell Ecosystem, Tianjin Institute of Immunology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Nat Chem Biol. 2022 Nov;18(11):1214-1223. doi: 10.1038/s41589-022-01128-x. Epub 2022 Aug 18.
The E3 ligase TRIM7 has emerged as a critical player in viral infection and pathogenesis. However, the mechanism governing the TRIM7-substrate association remains to be defined. Here we report the crystal structures of TRIM7 in complex with 2C peptides of human enterovirus. Structure-guided studies reveal the C-terminal glutamine residue of 2C as the primary determinant for TRIM7 binding. Leveraged by this finding, we identify norovirus and SARS-CoV-2 proteins, and physiological proteins, as new TRIM7 substrates. Crystal structures of TRIM7 in complex with multiple peptides derived from SARS-CoV-2 proteins display the same glutamine-end recognition mode. Furthermore, TRIM7 could trigger the ubiquitination and degradation of these substrates, possibly representing a new Gln/C-degron pathway. Together, these findings unveil a common recognition mode by TRIM7, providing the foundation for further mechanistic characterization of antiviral and cellular functions of TRIM7.
E3 连接酶 TRIM7 已成为病毒感染和发病机制中的关键因素。然而，调节 TRIM7-底物结合的机制仍有待确定。在这里，我们报告了 TRIM7 与人类肠道病毒 2C 肽复合物的晶体结构。结构导向研究揭示了 2C 的 C 末端谷氨酰胺残基是 TRIM7 结合的主要决定因素。利用这一发现，我们鉴定了诺如病毒和 SARS-CoV-2 蛋白以及生理蛋白是新的 TRIM7 底物。TRIM7 与源自 SARS-CoV-2 蛋白的多种肽的复合物的晶体结构显示出相同的谷氨酰胺末端识别模式。此外，TRIM7 可以触发这些底物的泛素化和降解，可能代表一种新的 Gln/C 降解途径。总之，这些发现揭示了 TRIM7 的一种常见识别模式，为进一步深入研究 TRIM7 的抗病毒和细胞功能的机制提供了基础。
