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

• Published in: Cell reports (Cambridge) Vol. 28; no. 9; pp. 2373 - 2385.e7
• Main Authors: Huang, Pei-Tzu, Summers, Brady James, Xu, Chaoyi, Perilla, Juan R., Malikov, Viacheslav, Naghavi, Mojgan H., Xiong, Yong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-08-2019; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Binding Sites; capsid; Capsid Proteins - chemistry; Capsid Proteins - metabolism; Cell Line; FEZ1; HIV; HIV-1 - pathogenicity; HIV-1 - physiology; Humans; kinesin adaptor protein; Microglia - metabolism; Microglia - virology; microtubule trafficking; Molecular Docking Simulation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; pattern sensing; Phytic Acid - metabolism; Protein Binding; Protein Transport; virus; HIV; FEZ1; capsid; pattern sensing; microtubule trafficking; kinesin adaptor protein; virus; CA
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.079

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.
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•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
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.