Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef⁺ viruses but not for down-regulation of CD4

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus Nef proteins contain a conserved motif with the minimal consensus (PxxP) site for Src homology region 3 (SH3)‐mediated protein‐protein interactions. Nef PxxP motifs show specific binding to biotinylated SH3 domains of Hck and Lyn, but not to those of other tested Src family kinases or less related proteins. A unique cooperative role of a distant proline is also observed. Endogenous Hck of monocytic U937 cells can be specifically precipitated by matrix‐bound HIV‐1 Nef, but not by mutant protein lacking PxxP. Intact Nef PxxP motifs are dispensable for Nef‐induced CD4 down‐regulation, but are required for the higher in vitro replicative potential of Nef⁺ viruses. Thus, CD4 down‐regulation and promotion of viral growth are two distinct functions of Nef, and the latter is mediated via SH3 binding.

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