Figure 1.

Structural model of HIV-1 Nef and major classes of membrane-associated host cell partners. The overall structure of Nef is modeled in the center with major structural features indicated. The myristoylated (Myr) N-terminal anchor domain, together with a patch of basic amino acids from the amphipathic helix, tether Nef to the plasma membrane. The membrane anchor connects to the folded core, which encompasses multiple motifs essential for host cell protein recruitment. Highlighted is the conserved PxxPxR motif, which is essential for both SH3 domain interaction and binding to the AP-1 endocytic adaptor. Also shown is the flexible internal loop, which engages AP-2. Major classes of membrane-associated partner proteins include nonreceptor tyrosine kinases of the Src and Tec families (left), which Nef activates to enhance the viral life cycle. Nef also interacts with the endocytic adaptor proteins AP-1 and AP-2 to prevent cell-surface expression of multiple proteins, including MHC-I, CD4, and SERINC5, to promote viral infectivity and immune escape. This model of full-length Nef at the membrane is adapted from Geyer and Peterlin (19).