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Mesoscale regulation of microtubule-organising centres by the E3 ligase TRIM37

ABSTRACT: 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 Microtubule-Organising Centres (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 thus far remained unknown. Here, we elucidate the activation process of TRIM37, unveiling a process that initiates with TRAF domain-directed substrate recognition, followed by B-box domain-mediated oligomerisation, and culminates in RING domain dimerisation. Using optogenetics, we demonstrate that the E3 activity of TRIM37 is directly coupled to the assembly state of its substrates, being activated only when centrosomal proteins cluster into higher-order assemblies resembling MTOCs. This regulatory framework provides a mechanistic basis for understanding TRIM37-driven pathologies and echoes the restriction of the HIV capsid by TRIM5, thus unveiling a conserved activation blueprint among TRIM proteins to control turnover of complexes assembled at the mesoscale level.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Mulibrey Nanism,Breast Cancer

SUBMITTER: Zhong YI Yeow

LAB HEAD: Andrew J Holland

PROVIDER: PXD061083 | Pride | 2025-03-18

REPOSITORIES: Pride

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	220227_HollandA_ZYY_Samples_Biotin.xml	Xml
	JP_CS_QE-220227_HollandA_ZYY_S1.raw	Raw
	JP_CS_QE-220227_HollandA_ZYY_S2.raw	Raw
	JP_CS_QE-220227_HollandA_ZYY_S3.raw	Raw
	JP_CS_QE-220227_HollandA_ZYY_S6.raw	Raw

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