Abstract
Members of the tripartite motif (TRIM) protein family of RING E3 ubiquitin (Ub) ligases promote innate immune responses by catalyzing synthesis of polyubiquitin chains linked through lysine 63 (K63). Here, we investigate the mechanism by which the TRIM5α retroviral restriction factor activates Ubc13, the K63-linkage-specific E2. Structural, biochemical, and functional characterization of the TRIM5α:Ubc13-Ub interactions reveals that activation of the Ubc13-Ub conjugate requires dimerization of the TRIM5α RING domain. Our data explain how higher-order oligomerization of TRIM5α, which is promoted by the interaction with the retroviral capsid, enhances the E3 Ub ligase activity of TRIM5α and contributes to its antiretroviral function. This E3 mechanism, in which RING dimerization is transient and depends on the interaction of the TRIM protein with the ligand, is likely to be conserved in many members of the TRIM family and may have evolved to facilitate recognition of repetitive epitope patterns associated with infection.
Highlights
tripartite motif (TRIM) proteins are defined by a conserved domain pattern, in which the RING module is located at the N terminus of the protein followed by one or two B-box domains and by a coiled-coil segment
Members of the tripartite motif (TRIM) protein family of RING E3 ubiquitin (Ub) ligases promote innate immune responses by catalyzing synthesis of polyubiquitin chains linked through lysine 63 (K63)
We investigate the mechanism by which the TRIM5a retroviral restriction factor activates Ubc13, the K63linkage-specific E2
Summary
TRIM proteins are defined by a conserved domain pattern, in which the RING module is located at the N terminus of the protein followed by one or two B-box domains and by a coiled-coil segment. Crystal structures of the TRIM25 and TRIM5a coiled-coil regions reveal the antiparallel coiledcoil hairpin architecture of the dimer, in which the RING and B-box domains of each monomer are located on the opposing ends of the rod-shaped, 170-A -long dimer, with the two SPRY domains positioned close to the middle of the coiled-coil rod (Goldstone et al, 2014; Sanchez et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
