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EMBO J. 2016 Jun 1;35(11):1204-18. doi: 10.15252/embj.201593741. Epub 2016 May 6.

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity.

Author information

1
Mill Hill Laboratory, Molecular Structure of Cell Signalling Laboratory, The Francis Crick Institute, London, UK.
2
Structural Biology Science Technology Platform, The Francis Crick Institute, London, UK.
3
Mill Hill Laboratory, Macromolecular Structure Laboratory, The Francis Crick Institute, London, UK.
4
Mill Hill Laboratory, Molecular Structure of Cell Signalling Laboratory, The Francis Crick Institute, London, UK katrin.rittinger@crick.ac.uk.

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.

KEYWORDS:

TRIM25; TRIM32; enzyme mechanism; protein structure; ubiquitin ligase

PMID:
27154206
PMCID:
PMC4864278
DOI:
10.15252/embj.201593741
[Indexed for MEDLINE]
Free PMC Article

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