A myristoyl switch regulates membrane binding of HIV-1 Gag

How and where are virus particles assembled in an infected cell? To address this question, virologists are studying retroviruses and lentiviruses, enveloped viruses that contain RNA as their genetic material. The only viral protein that is needed to make a virus-like particle is the Gag protein (1, 2). In the lentivirus HIV-1, Gag is synthesized as a cytosolic 55-kDa precursor (Pr55gag) that contains four domains: p17 matrix (MA), p24 capsid (CA), p7 nucleocapsid (NC), and p6 (Fig. 1A). The newly synthesized Gag precursor targets to the plasma membrane in most cells, where it multimerizes by means of its CA and NC domains into large arrays that direct particle assembly and budding. How does HIV-1 Gag associate with cellular membranes? The membrane-binding (M) domain maps to the N-terminal region of MA. For the M domain to function, it must be covalently modified at its N terminus by myristate, a 14-carbon saturated fatty acid (3). Nearly all mammalian retroviral Gag proteins are myristoylated (4). However, myristoylation alone is not sufficient to promote stable membrane binding of proteins (5, 6). A second signal, which in the case of HIV-1 Gag is a cluster of basic residues within the M domain, synergizes with myristate to promote tight membrane binding (7). Structural studies of non-myristoylated forms of MA have revealed that part of the M domain forms an amphipathic β-pleated sheet, with the basic residues oriented on the top surface (8–10). Here they would be positioned to interact electrostatically with negatively charged headgroups of acidic phospholipids in the membrane. But where is the myristate? The article by Tang et al. in this issue of PNAS (11 …