@article{693b97df415a4016b663a411ce2a1823,
title = "FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking",
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.",
keywords = "CA, FEZ1, HIV, capsid, kinesin adaptor protein, microtubule trafficking, pattern sensing, virus",
author = "Huang, {Pei Tzu} and Summers, {Brady James} and Chaoyi Xu and Perilla, {Juan R.} and Viacheslav Malikov and Naghavi, {Mojgan H.} and Yong Xiong",
note = "Funding Information: To test the hypothesis that FEZ1 contains multiple capsid-binding sites, we performed binding assays at low ionic strength conditions under which the low-affinity electrostatic interactions may sustain. Even at a low-salt condition of 50 mM NaCl, FEZ1 ). However, they efficiently copelleted with CA tubes under this condition ( 1–92 and FEZ1 198–392 did not coelute with CA hexamers in SEC-binding assays ( Figures 4 A and 4B Figure 4 C). These data show that the individual interactions in these auxiliary regions are weak but multiple interactions allowed avid binding to CA tubes. We confirmed that these sites also interact with CA hexamers at the R18 location, because the CA R18D mutation abolished or severely abrogated binding by all FEZ1 constructs ( Figure 4 C). A binding mode of this nature is supported by the salt dependence of CA tube binding by FEZ1 constructs ( Figures 4 E and 4F). A longer construct with more capsid-interacting stretches, FEZ1 92–227 , was able to retain binding in the presence of higher salt concentrations compared with a shorter construct with fewer binding stretches, FEZ1 92–158 . These results support a model in which primary hexamer-targeting motifs in FEZ1 (FEZ1 158–198 ) drive FEZ1-capsid interaction through avidity, with auxiliary binding provided by additional FEZ1 acidic stretches ( Figure 4 D). Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = aug,
day = "27",
doi = "10.1016/j.celrep.2019.07.079",
language = "English (US)",
volume = "28",
pages = "2373--2385.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",
}
