The HIV-1 envelope glycoprotein gp120 features four heparan sulfate binding domains, including the co-receptor binding site.
It is well established that the human immunodeficiency virus-1 envelope glycoprotein surface unit, gp120, binds to cell-associated heparan sulfate (HS). Virus infectivity is increased by such interaction, and a variety of soluble polyanions efficiently neutralize immunodeficiency virus-1 in vitro. This interaction has been mainly attributed to the gp120 V3 loop. However, although evidence suggested that this particular domain does not fully recapitulate the binding activity of the protein, the ability of HS to bind to other regions of gp120 has not been completely addressed, and the exact localizations of the polysaccharide binding sites are not known. To investigate in more detail the structural basis of the HS-gp120 interaction, we used a mapping strategy and compared the heparin binding activity of wild type and mutant gp120 using surface plasmon resonance-based binding assays. Four heparin binding domains (1-4) were identified in the V2 and V3 loops, in the C-terminal domain, and within the CD4-induced bridging sheet. Interestingly, three of them were found in domains of the protein that undergo structural changes upon binding to CD4 and are involved in co-receptor recognition. In particular, Arg(419), Lys(421), and Lys(432), which directly interact with the co-receptor, are targeted by heparin. This study provides a complete account of the gp120 residues involved in heparin binding and identified several binding surfaces that constitute potential target for viral entry inhibition.
Crublet
Elodie
E
Institut de Biologie Structurale, CNRS-Commissariat à l'Energie Atomique-Université Joseph Fourier, UMR 5075, 41 rue Horowitz, Grenoble, France.
Andrieu
Jean-Pierre
JP
Vivès
Romain R
RR
Lortat-Jacob
Hugues
H
D000818:Animals; D015704:CD4 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D010449:Peptide Mapping / Q000379:methods; D011485:Protein Binding / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D018411:Spodoptera; D020349:Surface Plasmon Resonance / Q000379:methods; D053586:Virus Internalization
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D006497:Heparan Sulfate; C514793:gp120 protein, Human immunodeficiency virus 1