Yeow Zhong Y, Sarju Sonia, Breugel Mark V, Holland Andrew J
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
School of Biological and Behavioural Sciences, Queen Mary University of London, London, E1 2AT, UK.
bioRxiv. 2024 Oct 9:2024.10.09.617407. doi: 10.1101/2024.10.09.617407.
Centrosomes ensure accurate chromosome segregation during cell division. Although the regulation of centrosome number is well-established, less is known about the suppression of non-centrosomal MTOCs (ncMTOCs). The E3 ligase TRIM37, implicated in Mulibrey nanism and 17q23-amplified cancers, has emerged as a key regulator of both centrosomes and ncMTOCs. Yet, the mechanism by which TRIM37 achieves enzymatic activation to target these mesoscale structures had remained unknown. Here, we elucidate TRIM37's activation process, beginning with TRAF domain-directed substrate recognition, progressing through B-box domain-mediated oligomerization, and culminating in RING domain dimerization. Using optogenetics, we demonstrate that TRIM37's E3 activity is directly coupled to the assembly state of its substrates, activating only when centrosomal proteins cluster into higher-order assemblies resembling MTOCs. This regulatory framework provides a mechanistic basis for understanding TRIM37-driven pathologies and, by echoing TRIM5's restriction of the HIV capsid, unveils a conserved activation blueprint among TRIM proteins for controlling mesoscale assembly turnover.
中心体确保细胞分裂过程中染色体的准确分离。尽管中心体数量的调控机制已得到充分确立，但对于非中心体微管组织中心（ncMTOCs）的抑制了解较少。E3连接酶TRIM37与穆利布雷侏儒症和17q23扩增癌症有关，已成为中心体和ncMTOCs的关键调节因子。然而，TRIM37实现酶促激活以靶向这些中尺度结构的机制仍不清楚。在这里，我们阐明了TRIM37的激活过程，从TRAF结构域导向的底物识别开始，通过B-box结构域介导的寡聚化，最终以RING结构域二聚化结束。利用光遗传学，我们证明TRIM37的E3活性直接与其底物的组装状态相关联，仅在中心体蛋白聚集成类似于MTOCs的高阶组装体时才被激活。这种调控框架为理解TRIM37驱动的病理学提供了机制基础，并且通过呼应TRIM5对HIV衣壳的限制，揭示了TRIM蛋白之间用于控制中尺度组装周转的保守激活蓝图。
