Dynamic conformational changes in the rhesus TRIM5α dimer dictate the potency of HIV-1 restriction.
The TRIM5α protein from rhesus macaques (rhTRIM5α) mediates a potent inhibition of HIV-1 infection via a mechanism that involves the abortive disassembly of the viral core. We have demonstrated that alpha-helical elements within the Linker 2 (L2) region, which lies between the SPRY domain and the Coiled-Coil domain, influence the potency of restriction. Here, we utilize single-molecule FRET analysis to reveal that the L2 region of the TRIM5α dimer undergoes dynamic conformational changes, which results in the displacement of L2 regions by 25 angstroms relative to each other. Analysis of restriction enhancing or abrogating mutations in the L2 region reveal that restriction defective mutants are unable to undergo dynamic conformational changes and do not assume compact, alpha-helical conformations in the L2 region. These data suggest a model in which conformational changes in the L2 region mediate displacement of CA bound SPRY domains to induce the destabilization of assembled capsid during restriction.
['Lamichhane|Rajan|R|', 'Mukherjee|Santanu|S|', 'Smolin|Nikolai|N|', 'Pauszek|Raymond F|RF|', 'Bradley|Margret|M|', 'Sastri|Jaya|J|', 'Robia|Seth L|SL|', 'Millar|David|D|', 'Campbell|Edward M|EM|']
D000595:Amino Acid Sequence D000818:Animals D002352:Carrier Proteins D002460:Cell Line D019281:Dimerization D004195:Disease Models, Animal D015658:HIV Infections D015497:HIV-1 D006801:Humans D008253:Macaca mulatta D009154:Mutation D011487:Protein Conformation
Dimer HIV-1 Coiled coil Molecular dynamics simulation Restriction factor Single molecule FRET TRIM5alpha Tripartite Motif smFRET