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J. Biol. Chem., Vol. 283, Issue 22, 15193-15200, May 30, 2008

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The HIV-1 Envelope Glycoprotein gp120 Features Four Heparan Sulfate Binding Domains, Including the Co-receptor Binding Site^*

From the Institut de Biologie Structurale, CNRS-Commissariat à l'Energie Atomique-Université Joseph Fourier, UMR 5075, 41 rue Horowitz, 38027 Grenoble, France

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, Arg⁴¹⁹, Lys⁴²¹, and Lys⁴³², 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.

Received for publication, January 3, 2008 , and in revised form, March 27, 2008.

^* This work was supported by the Agence Nationale de la Recherche sur le Syndrome d'Immunodéficience Acquise (ANRS), the CNRS, and the Commisariat à l'Energie Atomique. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by a doctoral fellowship from the ANRS and Sidaction.

² These authors contributed equally to the supervision of this study.

³ To whom correspondence should be addressed. Tel.: 33-438-784-485; Fax: 33-438-785-494; E-mail: Hugues.Lortat-Jacob{at}ibs.fr.

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