TRIM5α: A Protean Architect of Viral Recognition and Innate Immunity

Figures

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  Figure 1. Insights into TRIM5α organization and sequence variability within the SPRY domain (a) Overview of canonical TRIM family RBCC motif with C-terminal SPRY domain. (b) Comparative analysis of TRIM5α sequences within the v1 loop (labeled 330–340, referencing human TRIM5α) from simian primates. The African green monkey clade contains a notable 20-amino acid duplication in the v1 loop, denoted as ‘+20′. Rapidly evolving residues are indicated with gray boxes. Reprinted from Ref. [61] under CC BY-NC 4.0. (c) The crystal structure of SPRY from the rhesus macaque (PDB: 4B3N). Variable loops 2–4 highlighted in pink (v2–v4). Missing v1 density depicted as ΔV1.

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  Figure 2. TRIM5α creates organized assemblies against CA. (a) The crystal structure of the BCC miniTRIM dimer (a biochemical and structurally friendly construct that preserves the integrated B-box/coiled-coil architecture of the full-length dimer) from PDB: 5EIU. (b) The BCC miniTRIM trimer from PDB: 5IEA. Arrows indicate coiled-coil domain shifts in relation to the B-box trimer, creating an arc of approximately 12° along this path. (c) Cryo-ET and subtomogram averaging of in vitro-assembled HIV-1 capsid tubes coated with hexagonal arrays of TRIM5α. Scale bars, 100 nm. A combined lattice map of TRIM5 dimers and trimers, with capsid hexamers colored in orange, TRIM dimers in cyan, and TRIM trimers in magenta. Reprinted from Ref. [42] under CC BY-NC 4.0.

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  Figure 3. The autoubiquitylation of TRIM5α on retroviral capsids involves intricate interactions between RBCC domains [78]. The trimerization of B-box domains allows RING domains to be brought into proximity, forming an asymmetric structure that allows the RING domain to function as the catalytic activator and the substrate of ubiquitin. This RING catalytic activity initiates ubiquitination by activating an E2~Ub conjugate, UBE2W-Ub, and monoubiquitinates the N-terminus of the free RING. UBE2N-Ub/V2 then favors this monoubiquitinated site and promotes the subsequent extension and further exchange of K63-linked polyubiquitin chains. B-box (yellow); RING (red); coiled-coil (green); K63 ubiquitin (purple).