Abstract
TRIM5 proteins are restriction factors that block retroviral infections by binding viral capsids and preventing reverse transcription. Capsid recognition is mediated by C-terminal domains on TRIM5α (SPRY) or TRIMCyp (cyclophilin A), which interact weakly with capsids. Efficient capsid recognition also requires the conserved N-terminal tripartite motifs (TRIM), which mediate oligomerization and create avidity effects. To characterize how TRIM5 proteins recognize viral capsids, we developed methods for isolating native recombinant TRIM5 proteins and purifying stable HIV-1 capsids. Biochemical and EM analyses revealed that TRIM5 proteins assembled into hexagonal nets, both alone and on capsid surfaces. These nets comprised open hexameric rings, with the SPRY domains centered on the edges and the B-box and RING domains at the vertices. Thus, the principles of hexagonal TRIM5 assembly and capsid pattern recognition are conserved across primates, allowing TRIM5 assemblies to maintain the conformational plasticity necessary to recognize divergent and pleomorphic retroviral capsids.
Highlights
Mammalian hosts have evolved a series of different innate immune strategies to combat retroviruses
TRIM5-21R and TRIM5-21RDSPRY both assembled into similar planar lattices of hexagonal rings, with inter-ring spacings and protein densities matching those of the previous 2D projection structures (Ganser-Pornillos et al, 2011)
Our studies further support the prevailing models that TRIM5 restriction factors bind directly to the surfaces of incoming retroviral capsids and that restriction susceptibility is dictated at the level of capsid recognition (Li et al, 2006; Ohkura et al, 2006; Perez-Caballero et al, 2005; Sebastian and Luban, 2005; Song et al, 2005a; Stremlau et al, 2004; 2005; 2006)
Summary
Mammalian hosts have evolved a series of different innate immune strategies to combat retroviruses (reviewed in [Altfeld and Gale, 2015; Bieniasz, 2003, 2004; Fitzgerald et al, 2014; Harris et al, 2012; Neil and Bieniasz, 2009; Rustagi and Gale, 2014; Sparrer and Gack, 2015; van Montfoort et al, 2014; Yoo et al, 2014]). These weak interactions are amplified by TRIM5 assembly into a higher-order hexagonal lattice, which positions arrays of SPRY/ CypA domains to interact with repeating epitopes on the capsid surfaces (Ganser-Pornillos et al, 2011; Li and Sodroski, 2008) This ’pattern recognition’ model has been supported by biochemical and structural analyses of a TRIM5 protein construct called TRIM5-21R, which is an artificial chimera in which the RING domain from human TRIM21 replaces the RING domain of rhesus TRIM5a (Diaz-Griffero et al, 2006a; Kar et al, 2008; Langelier et al, 2008). These reagents were used to demonstrate that TRIM5 proteins form hexagonal arrays on HIV-1 capsids
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