Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity |
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| Authors: | Evangelos Christodoulou Ian A Taylor Katrin Rittinger |
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| Institution: | 1. Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK;2. Mill Hill Laboratory, Macromolecular Structure Laboratory, The Francis Crick Institute, London, UK;3. Mill Hill Laboratory, Molecular Structure of Cell Signalling Laboratory, The Francis Crick Institute, London, UK |
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| Abstract: | TRIM E3 ubiquitin ligases regulate a wide variety of cellular processes and are particularly important during innate immune signalling events. They are characterized by a conserved tripartite motif in their N‐terminal portion which comprises a canonical RING domain, one or two B‐box domains and a coiled‐coil region that mediates ligase dimerization. Self‐association via the coiled‐coil has been suggested to be crucial for catalytic activity of TRIMs; however, the precise molecular mechanism underlying this observation remains elusive. Here, we provide a detailed characterization of the TRIM ligases TRIM25 and TRIM32 and show how their oligomeric state is linked to catalytic activity. The crystal structure of a complex between the TRIM25 RING domain and an ubiquitin‐loaded E2 identifies the structural and mechanistic features that promote a closed E2~Ub conformation to activate the thioester for ubiquitin transfer allowing us to propose a model for the regulation of activity in the full‐length protein. Our data reveal an unexpected diversity in the self‐association mechanism of TRIMs that might be crucial for their biological function. |
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| Keywords: | enzyme mechanism protein structure TRIM25 TRIM32 ubiquitin ligase |
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