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HIV-1 matrix-tRNA complex structure reveals basis for host control of Gag localization
Cell Host & Microbe  (IF21.023),  Pub Date : 2021-08-11, DOI: 10.1016/j.chom.2021.07.006
Charles Bou-Nader, Frauke Muecksch, Janae B. Brown, Jackson M. Gordon, Ashley York, Chen Peng, Rodolfo Ghirlando, Michael F. Summers, Paul D. Bieniasz, Jinwei Zhang

The 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.