Dynamic conformational changes in the rhesus TRIM5α dimer dictate the potency of HIV-1 restriction

Rajan Lamichhane1, Santanu Mukherjee2, Nikolai Smolin3

  • 1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.

Virology
|November 9, 2016
PubMed

Insights

Rhesus TRIM-alpha5 (rhTRIM5α) protein restricts HIV-1 by destabilizing the viral core. Dynamic conformational changes in its L2 region are crucial for this antiviral restriction mechanism.

Area of Science:

  • Virology
  • Structural Biology
  • Immunology

Background:

  • The TRIM5α protein from rhesus macaques (rhTRIM5α) inhibits HIV-1 infection.
  • This inhibition involves the premature disassembly of the viral core.
  • Alpha-helical elements in the Linker 2 (L2) region of TRIM5α affect its restriction potency.

Purpose of the Study:

  • To investigate the dynamic conformational changes in the L2 region of rhTRIM5α.
  • To understand the role of these conformational changes in HIV-1 restriction.

Main Methods:

  • Single-molecule Förster Resonance Energy Transfer (smFRET) analysis.
  • Analysis of restriction-modulating mutations in the L2 region.

Main Results:

  • The L2 region of rhTRIM5α dimers undergoes dynamic conformational changes, displacing L2 regions by 25 angstroms.
  • Mutations that impair restriction prevent these dynamic changes and stable alpha-helical conformations in the L2 region.

Conclusions:

  • Conformational changes in the L2 region are essential for rhTRIM5α's antiviral activity.
  • These changes likely mediate the displacement of SPRY domains, leading to capsid destabilization and HIV-1 restriction.