Does it take two to tango? RING domain self-association and activity in TRIM E3 ubiquitin ligases.

Filippo Fiorentini,Diego Esposito,Katrin Rittinger

doi:10.1042/bst20200383

Filippo Fiorentini, Diego Esposito + Show 1 more

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https://doi.org/10.1042/bst20200383

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Journal: Biochemical Society transactions	Publication Date: Nov 10, 2020
Citations: 30	License type: CC BY 4.0

Affiliation: The Francis Crick Institute

Abstract

TRIM proteins form a protein family that is characterized by a conserved tripartite motif domain comprising a RING domain, one or two B-box domains and a coiled-coil region. Members of this large protein family are important regulators of numerous cellular functions including innate immune responses, transcriptional regulation and apoptosis. Key to their cellular role is their E3 ligase activity which is conferred by the RING domain. Self-association is an important characteristic of TRIM protein activity and is mediated by homodimerization via the coiled-coil region, and in some cases higher order association via additional domains of the tripartite motif. In many of the TRIM family proteins studied thus far, RING dimerization is an important prerequisite for E3 ligase enzymatic activity though the propensity of RING domains to dimerize differs significantly between different TRIMs and can be influenced by other regions of the protein.

Highlights

An abundance of cellular functions is controlled by the attachment of a 76-residue ubiquitin (Ub) molecule to a protein substrate
We discuss the role of the catalytic RING domain in TRIM ligase function and recent advancements in the understanding of the mechanistic details that lie at the basis of its ubiquitination activity
The ability of the TRIM32 RING domain to self-associate is both necessary and sufficient for its catalytic activity: the deletion of the N- and C-terminal helices produces a monomeric form of the protein, whose NMR solution structure has been determined (PDB: 2CT2), and which lacks any detectable E3 ligase activity [25]

Summary

Introduction

An abundance of cellular functions is controlled by the attachment of a 76-residue ubiquitin (Ub) molecule to a protein substrate. In all TRIM family RINGs that have been shown to self-associate, but TRIM19, RING dimerization is achieved via hydrophobic interactions between aliphatic side chains of residues present in short α-helical segments at the N- and C-termini of the zinc-coordinating core RING domain that form a 4-helix bundle.

Results

Conclusion