Bou-Nader, CharlesMuecksch, FraukeBrown, Janae B.Gordon, Jackson M.York, AshleyPeng, ChenGhirlando, RodolfoSummers, Michael2021-08-242021-08-242021-08-11Bou-Nader, Charles et al.; HIV-1 matrix-tRNA complex structure reveals basis for host control of Gag localization; Cell Host & Microbe, 11 August, 2021; https://doi.org/10.1016/j.chom.2021.07.006https://doi.org/10.1016/j.chom.2021.07.006http://hdl.handle.net/11603/22673The HIV-1 virion structural polyprotein, Gag, is directed to particle assembly sites at the plasma membrane by its N-terminal matrix (MA) domain. MA also binds to host tRNAs. To understand the molecular basis of MA-tRNA interaction and its potential function, we present a co-crystal structure of HIV-1 MA-tRNALys3 complex. The structure reveals a specialized group of MA basic and aromatic residues preconfigured to recognize the distinctive structure of the tRNA elbow. Mutational, cross-linking, fluorescence, and NMR analyses show that the crystallographically defined interface drives MA-tRNA binding in solution and living cells. The structure indicates that MA is unlikely to bind tRNA and membrane simultaneously. Accordingly, single-amino-acid substitutions that abolish MA-tRNA binding caused striking redistribution of Gag to the plasma membrane and reduced HIV-1 replication. Thus, HIV-1 exploits host tRNAs to occlude a membrane localization signal and control the subcellular distribution of its major structural protein.5 filesen-USThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)https://creativecommons.org/licenses/by-nc-nd/4.0/Text