Abstract
Tripartite motif-containing (TRIM) proteins are defined by the sequential arrangement of RING, B-box and coiled-coil domains (RBCC), where the B-box domain is a unique feature of the TRIM protein family. TRIM21 is an E3 ubiquitin-protein ligase implicated in innate immune signaling by acting as an autoantigen and by modifying interferon regulatory factors. Here we report the three-dimensional solution structure of the TRIM21 B-box2 domain by nuclear magnetic resonance (NMR) spectroscopy. The structure of the B-box2 domain, comprising TRIM21 residues 86–130, consists of a short α-helical segment with an N-terminal short β-strand and two anti-parallel β-strands jointly found the core, and adopts a RING-like fold. This ββαβ core largely defines the overall fold of the TRIM21 B-box2 and the coordination of one Zn2+ ion stabilizes the tertiary structure of the protein. Using NMR titration experiments, we have identified an exposed interaction surface, a novel interaction patch where the B-box2 is likely to bind the N-terminal RING domain. Our structure together with comparisons with other TRIM B-box domains jointly reveal how its different surfaces are employed for various modular interactions, and provides extended understanding of how this domain relates to flanking domains in TRIM proteins.
Highlights
Ubiquitination is a vital post-translation modification for many cellular processes including protein turnover in the cell, cell-cycle control, transcriptional regulation, intracellular signaling and innate immunity [1,2]
We present the solution structure of the TRIM21 B-box2 domain, and show how this entity interacts with its corresponding TRIM21 Really Interesting New Gene (RING) domain
Initial structures were determined based on NOE restraints only, in the absence of additional zinc ion restraints in order to not nuclear magnetic resonance (NMR) structure of TRIM21 B-box2 and its RING interactions bias the fold of the domain
Summary
Ubiquitination is a vital post-translation modification for many cellular processes including protein turnover in the cell, cell-cycle control, transcriptional regulation, intracellular signaling and innate immunity [1,2]. Protein ubiquitination is a multi-enzyme process involving the attachment of the small protein ubiquitin to target proteins. The ubiquitin-signaling pathway involves a cascade of enzymes—E1 activating enzyme, E2 conjugating enzyme, and E3 ligase– and results in the attachment of ubiquitin on the substrate or on a growing polyubiquitin. NMR structure of TRIM21 B-box and its RING interactions. Foundation for International Cooperation in Research and Higher Education (BW, MS)
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