Both lipid environment and pH are critical for determining physiological solution structure of 3-D-conserved epitopes of the HIV-1 gp41-MPER peptide P1

Abstract : In terms of background, the solutionstructure of monomeric peptide P1 (residues 649 – 683),located in the conserved membrane proximal region(MPER) of HIV-1 envelope glycoprotein gp41, is firstreported here in dodecylphosphocholine (DPC) micelles.P1 is the minimal MPER region that permits interactionwith the mucosal galactosyl ceramide HIV-receptor; it alsocontains epitopes recognized by major gp41-specific,broadly neutralizing immunoglobulin Gs (IgGs), 2F5 and4E10, determinant in HIV fusion/infection. Our principalfindings were as follows: the structural stability of P1 ispH dependent, as the-helix comprising Q653 I682,present at pH 3.3, is destabilized at higher pH values. AtpH 6, the E-rich N-terminal half of P1 (residues 650 –666), partially overlapping the 2F5-specific epitope, be-comes fully disordered, while the W-rich C-terminal halfconserves two shorter helices (W666 –W670 and W672–W680), separated by a well-defined bend overlapped bythe 4E10-specific epitope. The two IgGs bind to P1 onDPC micelles with binding parameters (Kd) in the nano-molar range. Next, P1 was derivatized with phosphati-dylethanolamine at its C terminal and inserted into lipo-somes of varied lipid composition, thereby enabling P1 tomove laterally. Alternatively, an infectious virus-bindingassay was established. TheKdof both 2F5 and 4E10 IgGsmeasured on viral liposome and virus are similar andmuch lower than for the binding of the free peptide. Inconclusion, P1, in a lipid environment, is an optimizedMPER-derived peptide suitable for designing an immuno-gen inducing broadly neutralizing antibodies to HIV.—Coutant, J., Yu, H., Cle ́ ment, M.-J., Alfsen, A., Toma, F.,Curmi, P. A., Bomsel, M. Both lipid environment and pHare critical for determining physiological solution struc-ture of 3-D-conserved epitopes of the HIV-1 gp41-MPERpeptide P1.
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Jérôme Coutant, Huifeng Yu, Marie-Jeanne Clément, Annette Alfsen, Flavio Toma, et al.. Both lipid environment and pH are critical for determining physiological solution structure of 3-D-conserved epitopes of the HIV-1 gp41-MPER peptide P1. FASEB Journal, Federation of American Society of Experimental Biology, 2008, 22 (12), pp.4338-4351. ⟨10.1096/fj.08-113142⟩. ⟨hal-02295314⟩

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