The binding of HIV-1 gp41 membrane proximal domain to its mucosal receptor, galactosyl ceramide, is structure-dependent.
The peptide of HIV-1 envelope gp41 (a.a 628-683), referred to herein as P5, contains P1, a conserved galactose-specific lectin domain for binding the mucosal HIV-1-receptor, galactosyl ceramide (GalCer), as shown earlier, and a potential calcium-binding site (a.a 628-648). P1 contains contiguous epitopes recognized by the broadly neutralizing antibodies 2F5, 4E10, Z13. However, similar neutralizing antibodies could not be raised in animal model using immunogens based on these epitopes. We now show that the structure of both P5 and P1 peptides, as measured by circular dichroism, differs according to their environment: aqueous or lipidic, and as a function of calcium concentration. P5, but not P1, binds to calcium with a low binding affinity constant in the order of 2.5x10(4). Calcium binding results in a conformational change of P5, leading in turn to a decrease in affinity for GalCer. Hence, the affinity of the gp41-lectin site for the galactose harbored by the mucosal HIV-1 receptor GalCer is modulated by the peptide secondary and tertiary structure and the local environment. Therefore, definition of the conformation of this novel extended gp41 membrane proximal region, containing the conserved peptide P1 and the Ca(2+) binding site, could help designing an immunogen efficient at inducing neutralizing anti-HIV-1 antibodies.
Yu
Huifeng
H
Entrée Muqueuse du VIH et Immunité Muqueuse, Département de Biologie Cellulaire, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 22 rue Méchain, 75014 Paris, France.
Alfsen
Annette
A
Tudor
Daniela
D
Bomsel
Morgane
M
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002942:Circular Dichroism; D005699:Galactosylceramides / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000821:virology; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D015728:Receptors, HIV / Q000378:metabolism*; D014364:Tryptophan / Q000032:analysis
D005699:Galactosylceramides; D015700:HIV Envelope Protein gp41; D010455:Peptides; D015728:Receptors, HIV; C514787:gp41 protein, Human immunodeficiency virus 1; D014364:Tryptophan; D002118:Calcium