HIV-1 matrix-tRNA complex structure reveals basis for host control of Gag localization

• Published in: Cell host & microbe 2021-09, Vol.29 (9), p.1421-1436.e7
• Main Authors: Bou-Nader, Charles, Muecksch, Frauke, Brown, Janae B., Gordon, Jackson M., York, Ashley, Peng, Chen, Ghirlando, Rodolfo, Summers, Michael F., Bieniasz, Paul D., Zhang, Jinwei
• Format: Article
• Language: English
• Subjects: assembly; Binding Sites; Cell Membrane - metabolism; Gag; gag Gene Products, Human Immunodeficiency Virus - metabolism; HEK293 Cells; HeLa Cells; HIV; HIV Antigens - metabolism; HIV-1 - genetics; host-pathogen; Humans; interactions; localization; matrix; plasma membrane; Protein Domains - physiology; RNA, Transfer - genetics; RNA, Transfer - metabolism; RNA-Binding Proteins - metabolism; RNA-protein interactions; tRNA; Virus Assembly - physiology
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2021.07.006

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. [Display omitted] •Co-crystal structure of HIV-1 Gag MA domain bound to human tRNALys3•MA specifically recognizes tRNA elbow structure•K32A or W36A in MA abolishes tRNA binding and redistributes Gag to plasma membrane•Inability of Gag to bind tRNA leads to reduced HIV-1 replication Host tRNAs interact with HIV-1 Gag matrix domain, which targets Gag to the plasma membrane. Bou-Nader et al. solve a co-crystal structure of HIV-1 matrix bound to human tRNALys3 and reveal that specific recognition of tRNA “elbow” allows HIV-1 to exploit host tRNAs to regulate Gag localization and virion assembly.