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

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-tRNA(Lys3) 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, andNMR 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.

Automated summary

The HIV-1 virion structural polyprotein Gag is directed to assembly sites by its N-terminal matrix domain, which also binds to host tRNAs. The co-crystal structure of the HIV-1 MA-tRNA(Lys3) complex reveals a specialized interface that facilitates binding in solution and living cells. Mutations disrupting this interaction cause Gag redistribution and reduced HIV-1 replication, indicating the virus's reliance on host tRNAs for subcellular localization control.