Characterization and molecular basis of the oligomeric structure of HIV-1 Nef protein

The Nef protein of human immunodeficiency virus type I (HIV-1) is an import ant determinant for the onset of AIDS disease. The self-association propert ies of HIV-1 Nef are analyzed by chemical cross-linking, dynamic light scat tering, equilibrium analytical ultracentrifugation, and NMR spectroscopy. T he experimental data show that the HN-I Nef core domain forms stable homo-d imers and trimers in solution, but not higher oligomers. These Nef homomers are not covalently linked by disulfide bridges, and the equilibrium betwee n these forms is dependent on the Nef concentration. We further provide the molecular basis for the Nef core dimers and trimers obtained by analysis o f crystallographic models. Oligomerization of biological polypeptides is a common tool used to trigger events in cellular signaling and endocytosis, b oth of which an targeted by Nef. The quaternary structure of Nef may be of physiological importance and may help to connect its cellular targets or to increase affinity of the viral molecule for its ligands. The herein descri bed models for Nef dimers and trimers will allow further mutational studies to elucidate their role in vivo. These results provide novel insight into the structural and functional relationships of this important viral protein . Moreover, the oligomer intel face may represent a novel target for the de sign of antiviral agents.