Structural investigation of the HIV-1 envelope glycoprotein gp160 cleavage site

The selective proteolytic activation of the HIV-1 envelope glycoprotein gp160 by furin and other precursor convertases (PCs) occurs at the carboxyl side of the sequence Arg508-Glu-Lys-Arg511 (site 1), in spite of the presence of another consensus sequence: Lys500-Ala-Lys-Arg503 (site 2). We report on the soln. structural anal. of a 19-residue synthetic peptide, p498, which spans the two gp160-processing sites 1 and 2, and is properly digested by furin at site 1. A mol. model is obtained for p498, by means of mol. dynamics simulations, from NMR data collected in trifluoroethanol/water. The peptide N-terminal side presents a 9-residue helical segment, enclosing the processing site 2; the C-terminal segment can be described as a loop exposing the processing site 1. A hypothesis for the docking of p498 onto the catalytic domain of human furin, modeled by homol. and fitting previous site-directed mutagenesis studies, is also presented. P498 site 1 is shown to have easy access to the furin catalytic site, unlike the nonphysiol. site 2. Finally, on the basis of available data, we suggest a possible structural motif required for the gp160 - PCs recognition.