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

Chemistry : a European Journal
Romina OlivaLivio Paolillo

Abstract

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 solution structural analysis 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 molecular model is obtained for p498, by means of molecular 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 homology 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 nonphysiological site 2. Finally, on the basis of available data, we suggest a possible structural motif required for the gp160-PCs recognition.

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Citations

Mar 3, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Lisa EgererDorothee von Laer
Feb 14, 2004·Journal of Virology·Poonsook KeelapangNopporn Sittisombut
Nov 27, 2007·FEBS Letters·A PasquatoC Di Bello
Nov 9, 2011·Journal of Molecular Biology·Geoffrey K FeldBryan A Krantz
Apr 25, 2013·Antiviral Research·Antonella PasquatoStefan Kunz
Nov 5, 2004·Chembiochem : a European Journal of Chemical Biology·Lucia FalcignoLivio Paolillo

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