Restriction of HIV-1 by rhesus TRIM5α is governed by alpha helices in the Linker2 region

Jaya Sastri, Laura Johnsen, Nikolai Smolin, Sabrina Imam, Santanu Mukherjee, Zana Lukic, Alberto Brandariz-Nuñez, Seth L. Robia, Felipe Diaz-Griffero, Christopher Wiethoff, Edward M. Campbell

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

TRIM5α proteins are a potent barrier to the cross-species transmission of retroviruses. TRIM5α proteins exhibit an ability to self-associate at many levels, ultimately leading to the formation of protein assemblies with hexagonal symmetry in vitro and cytoplasmic assemblies when expressed in cells. However, the role of these assemblies in restriction, the determinants that mediate their formation, and the organization of TRIM5α molecules within these assemblies have remained unclear. Here we show that α-helical elements within the Linker2 region of rhesus macaque TRIM5α govern the ability to form cytoplasmic assemblies in cells and restrict HIV-1 infection. Mutations that reduce α-helix formation by the Linker2 region disrupt assembly and restriction. More importantly, mutations that enhance the α-helical content of the Linker2 region, relative to the wild-type protein, also exhibit an increased ability to form cytoplasmic assemblies and restrict HIV-1 infection. Molecular modeling of the TRIM5α dimer suggests a model in which α-helical elements within the Linker2 region dock to α-helices of the coiled-coil domain, likely establishing proper orientation and spacing of protein domains necessary for assembly and restriction. Collectively, these studies provide critical insight into the determinants governing TRIM5α assembly and restriction and demonstrate that the antiviral potency of TRIM5α proteins can be significantly increased without altering the affinity of SPRY/capsid binding.

Original languageEnglish (US)
Pages (from-to)8911-8923
Number of pages13
JournalJournal of virology
Volume88
Issue number16
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Sastri, J., Johnsen, L., Smolin, N., Imam, S., Mukherjee, S., Lukic, Z., Brandariz-Nuñez, A., Robia, S. L., Diaz-Griffero, F., Wiethoff, C., & Campbell, E. M. (2014). Restriction of HIV-1 by rhesus TRIM5α is governed by alpha helices in the Linker2 region. Journal of virology, 88(16), 8911-8923. https://doi.org/10.1128/JVI.01134-14