Cell Reports
Volume 28, Issue 9, 27 August 2019, Pages 2373-2385.e7
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Article
FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking

https://doi.org/10.1016/j.celrep.2019.07.079Get rights and content
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Highlights

  • Kinesin adaptor protein FEZ1 directly interacts with HIV-1 capsid for trafficking

  • FEZ1 specifically targets the conserved center pore of capsid protein (CA) hexamers

  • FEZ1 uses electrostatic interactions to bind multiple CA hexamers in the capsid

  • FEZ1 capsid-binding residues are important for HIV-1 trafficking and infectivity

Summary

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.

Keywords

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

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These authors contributed equally

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