Abstract
The tripartite-motif protein, TRIM5α, is an innate immune sensor that potently restricts retrovirus infection by binding to human immunodeficiency virus capsids. Higher-ordered oligomerization of this protein forms hexagonally patterned structures that wrap around the viral capsid, despite an anomalously low affinity for the capsid protein (CA). Several studies suggest TRIM5α oligomerizes into a lattice with a symmetry and spacing that matches the underlying capsid, to compensate for the weak affinity, yet little is known about how these lattices form. Using a combination of computational simulations and electron cryo-tomography imaging, we reveal the dynamical mechanisms by which these lattices self-assemble. Constrained diffusion allows the lattice to reorganize, whereas defects form on highly curved capsid surfaces to alleviate strain and lattice symmetry mismatches. Statistical analysis localizes the TRIM5α binding interface at or near the CypA binding loop of CA. These simulations elucidate the molecular-scale mechanisms of viral capsid cellular compartmentalization by TRIM5α.
Highlights
The tripartite-motif protein, TRIM5α, is an innate immune sensor that potently restricts retrovirus infection by binding to human immunodeficiency virus capsids
Given the low affinity of individual TRIM5α monomers for the capsid, how does TRIM5α effectively encage the viral capsid? Dimerization enhances TRIM5α binding in vitro, and several studies, including ours, have suggested that the weak interactions are amplified by avidity effects resulting from higher-ordered oligomerization, which positions the SPRY domains to interact with repeating structural elements on the capsid surface[22,23]; none have explored the dynamics of how this might occur
To surmount the computational cost associated with simulations at an atomic level of detail, we developed a CG model for TRIM5α self-assembly on viral capsids, using methods established in prior studies[25,26,27,28]
Summary
The tripartite-motif protein, TRIM5α, is an innate immune sensor that potently restricts retrovirus infection by binding to human immunodeficiency virus capsids. Higher-ordered oligomerization of this protein forms hexagonally patterned structures that wrap around the viral capsid, despite an anomalously low affinity for the capsid protein (CA). Statistical analysis localizes the TRIM5α binding interface at or near the CypA binding loop of CA These simulations elucidate the molecular-scale mechanisms of viral capsid cellular compartmentalization by TRIM5α. Dimerization enhances TRIM5α binding in vitro, and several studies, including ours, have suggested that the weak interactions are amplified by avidity effects resulting from higher-ordered oligomerization, which positions the SPRY domains to interact with repeating structural elements on the capsid surface[22,23]; none have explored the dynamics of how this might occur. We investigate the self-assembly mechanisms of TRIM5α on the HIV-1 retroviral capsid, using a combined coarse-grained (CG) molecular simulation, cryo-electron tomography (cryo-ET) imaging, and computational analysis approach
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