FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking

Pei Tzu Huang, Brady James Summers, Chaoyi Xu, Juan R. Perilla, Viacheslav Malikov, Mojgan H. Naghavi, Yong Xiong*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

HIV-1 uses the microtubule network to traffic the viral capsid core toward the nucleus. Viral nuclear trafficking and infectivity require the kinesin-1 adaptor protein FEZ1. Here, we demonstrate that FEZ1 directly interacts with the HIV-1 capsid and specifically binds capsid protein (CA) hexamers. FEZ1 contains multiple acidic, poly-glutamate stretches that interact with the positively charged central pore of CA hexamers. The FEZ1-capsid interaction directly competes with nucleotides and inositol hexaphosphate (IP6) that bind at the same location. In addition, all-atom molecular dynamic (MD) simulations establish the molecular details of FEZ1-capsid interactions. Functionally, mutation of the FEZ1 capsid-interacting residues significantly reduces trafficking of HIV-1 particles toward the nucleus and early infection. These findings support a model in which the central capsid hexamer pore is a general HIV-1 cofactor-binding hub and FEZ1 serves as a unique CA hexamer pattern sensor to recognize this site and promote capsid trafficking in the cell. In this paper, Huang et al. find that the viral cofactor FEZ1, a kinesin adaptor protein, uses multiple negatively charged amino-acid stretches to avidly interact with the positive center pores of the HIV-1 capsid protein hexamers, associating the virus particles to kinesin motors and thus promoting viral trafficking and infection.

Original languageEnglish (US)
Pages (from-to)2373-2385.e7
JournalCell reports
Volume28
Issue number9
DOIs
StatePublished - Aug 27 2019

Keywords

  • CA
  • FEZ1
  • HIV
  • capsid
  • kinesin adaptor protein
  • microtubule trafficking
  • pattern sensing
  • virus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Huang, P. T., Summers, B. J., Xu, C., Perilla, J. R., Malikov, V., Naghavi, M. H., & Xiong, Y. (2019). FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking. Cell reports, 28(9), 2373-2385.e7. https://doi.org/10.1016/j.celrep.2019.07.079