Structural Investigation of the HIV-1 Envelope Glycoprotein gp160 Cleavage Site 3: Role of Site-Specific Mutations

Proteolytic processing of HIV gp160 to produce gp120 and gp41 is performed by PC enzymes. This process is a prerequisite for the virus infectivity, since both gp120 and gp41 participate in the virus HIV-1 entry mechanism. The structure of the gp120/gp41 junction remains to be elucidated, and the str...

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Published in:Chembiochem : a European journal of chemical biology 2004-12, Vol.5 (12), p.1653-1661
Main Authors: Falcigno, Lucia, Oliva, Romina, D'Auria, Gabriella, Maletta, Massimiliano, Dettin, Monica, Pasquato, Antonella, Di Bello, Carlo, Paolillo, Livio
Format: Article
Language:English
Subjects:
Catalytic Domain
conformation analysis
D-amino acids
Furin - pharmacology
gp160
HIV
HIV Envelope Protein gp160 - chemistry
HIV Envelope Protein gp160 - metabolism
HIV-1 - chemistry
Human immunodeficiency virus 1
Humans
Mutagenesis, Site-Directed
NMR spectroscopy
Peptide Fragments - chemistry
Point Mutation
Proline - chemistry
Protein Conformation - drug effects
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Summary:Proteolytic processing of HIV gp160 to produce gp120 and gp41 is performed by PC enzymes. This process is a prerequisite for the virus infectivity, since both gp120 and gp41 participate in the virus HIV-1 entry mechanism. The structure of the gp120/gp41 junction remains to be elucidated, and the structural features required for molecular recognition between HIV-1 gp160 and proteolytic enzymes have not been clarified. Furin is the best PC candidate for the gp160 proteolytic processing known to date. In previous studies on model peptides, we have shown the relevance of an N-terminal helix for the proper recognition of the gp160 processing site by furin. Here we analyze the effect of point mutations in peptides lacking a regular N-terminal helix. To this end, we present the structure-activity characterization of three peptide analogues of the HIV gp160 processing site that all present mutations in proline at positions P3 and/or P2′, while sharing the same N-terminal sequence, containing helix-breaking D-amino acids. Conformational analysis of the peptides was carried out in solution by NMR techniques, and furin's efficiency in cleaving them was measured. Structural findings are presented and discussed in relation to the different exhibited activity.
ISSN:1439-4227
1439-7633
1439-4227
DOI:10.1002/cbic.200400181