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 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.
Oliva
Romina
R
Dipartimento di Chimica, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, via Cintia, 80126 Napoli, Italy.
Leone
Marilisa
M
Falcigno
Lucia
L
D'Auria
Gabriella
G
Dettin
Monica
M
Scarinci
Claudia
C
Di Bello
Carlo
C
Paolillo
Livio
L
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D016384:Consensus Sequence; D045683:Furin; D019302:HIV Envelope Protein gp160 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012996:Solutions; D013381:Subtilisins / Q000737:chemistry* / Q000378:metabolism
D019302:HIV Envelope Protein gp160; D010446:Peptide Fragments; D012996:Solutions; D013381:Subtilisins; D045683:Furin