The B30.2(SPRY) Domain of the Retroviral Restriction Factor TRIM5α Exhibits Lineage-Specific Length and Sequence Variation in Primates

Abstract

Tripartite motif (TRIM) proteins are composed of RING, B-box 2, and coiled coil domains. Some TRIM proteins, such as TRIM5␣, also possess a carboxy-terminal B30.2(SPRY) domain and localize to cytoplasmic bodies. TRIM5␣ has recently been shown to mediate innate intracellular resistance to retroviruses, an activity dependent on the integrity of the B30.2 domain, in particular primate species. An examination of the sequences of several TRIM proteins related to TRIM5 revealed the existence of four variable regions (v1, v2, v3, and v4) in the B30.2 domain. Species-specific variation in TRIM5␣ was analyzed by amplifying, cloning, and sequencing nonhuman primate TRIM5 orthologs. Lineage-specific expansion and sequential duplication occurred in the TRIM5␣ B30.2 v1 region in Old World primates and in v3 in New World monkeys. We observed substitution patterns indicative of selection bordering these particular B30.2 domain variable elements. These results suggest that occasional, complex changes were incorporated into the TRIM5␣ B30.2 domain at discrete time points during the evolution of primates. Some of these time points correspond to periods during which primates were exposed to retroviral infections, based on the appearance of particular endogenous retroviruses in primate genomes. The results are consistent with a role for TRIM5␣ in innate immunity against retroviruses.

TRIM5α Cytoplasmic Bodies Are Highly Dynamic Structures

“…In addition, the dynamic nature of these TRIM5␣ cytoplasmic bodies, as measured by FRAP, is similar to FRAP recovery performed on nuclear PML bodies (Rivera et al, 2003;Dong et al, 2004). In PML, it is thought that nuclear body formation is critical to PML function, because a well-characterized genetic translocation resulting in a fusion protein between PML and the retinoic acid receptor ␣ results in the disruption of PML nuclear bodies and the induction of acute promelocytic leukemia (Song et al, 2005b). Although TRIM5␣ is not associated with the cytoplasmic P-bodies (Figure 2), both structures exhibit similar dynamics of protein exchanges between individual structures and associate with microtubules (Leung et al, 2006;Sweet et al, 2007).…”

“…Small amino acid substitutions between the SPRY domain of rhTRIM5␣ and huTRIM5␣ has been sufficient to derive huTRIM5␣ variants capable of restricting HIV-1 infection (Stremlau et al, 2005;Yap et al, 2005). The importance of this region is further underscored by evidence that these same residues that confer species-specific restriction within the SPRY domain have been positively selected during the course of primate evolution (Sawyer et al, 2005;Song et al, 2005b), suggesting that TRIM5␣ has been at the forefront of the battle between primates and retroviruses for millions of years. Although the regions and residues within TRIM5␣ required for retroviral restriction have been identified, much less is known about the cell biology of TRIM5␣ and the mechanism by which it is able to inhibit infection by a retrovirus.…”

Generation of human TRIM5α mutants with high HIV-1 restriction activity

“…33 Humans, chimpanzees and gorillas are the only known primates to have a positively charged residue at this position. 31 Partly for that reason, the role of this residue in the inability of TRIM5a hu to restrict HIV-1 had been suspected before, 45 but data published so far has suggested that it was only a minor determinant of HIV-1 restriction. For instance, TRIM5a rh with an arginine at this position instead of a leucine was still fully able to restrict HIV-1.…”

“…30 PRYSPRY is the most variable domain of TRIM5a, and it contains four highly variable regions (see Figure 1d), labeled v1-v4, 31 although only v1-v3 are generally considered relevant to restriction specificity. Construction of chimeric genes in which these three variable regions are swapped between TRIM5a orthologues showed that all three of them can potentially contribute to restriction specificity.…”

Ovine TRIM5α Can Restrict Visna/Maedi Virus

“…TRIM5 family members bear a RING-B-box-coiled-coil structure consisting of an N-terminal RING domain (with E3 ubiquitin ligase activity), a B-box domain, and a coiled-coil domain (19). The TRIM5␣ isoform, which is active against retroviruses, contains a C-terminal PRYSPRY domain that binds retroviral capsid CA (12,20,35). This interaction, involving amino acid 332 of TRIM5␣ in humans (15) and 334 in monkeys, may explain the high relative rates of nonsynonymous changes of the primate TRIM5␣ gene (13).…”