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Título: | Functional Delineation of a Protein-Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8 |
Autor: | Insausti, Sara CSIC ORCID; García-Porras, Miguel CSIC; Torralba, Johana CSIC; Morillo, Izaskun CSIC ORCID; Ramos Caballero, Ander; Arada, Igor de la CSIC ORCID; Apellániz, Beatriz CSIC ORCID; Caaveiro, José M. M.; Carravilla, Pablo CSIC ORCID; Eggeling, Christian; Rujas, Edurne CSIC ORCID; Nieva, José Luis CSIC ORCID | Palabras clave: | MPER epitope recognition Protein–membrane interactions Antibody–membrane interactions Anti-MPER HIV antibody IV neutralization Broadly neutralizing antibody 10E8 |
Fecha de publicación: | sep-2022 | Editor: | Multidisciplinary Digital Publishing Institute | Citación: | International Journal of Molecular Sciences 23(18): 10767 (2022) | Resumen: | Antibody engagement with the membrane-proximal external region (MPER) of the envelope glycoprotein (Env) of HIV-1 constitutes a distinctive molecular recognition phenomenon, the full appreciation of which is crucial for understanding the mechanisms that underlie the broad neutralization of the virus. Recognition of the HIV-1 Env antigen seems to depend on two specific features developed by antibodies with MPER specificity: (i) a large cavity at the antigen-binding site that holds the epitope amphipathic helix; and (ii) a membrane-accommodating Fab surface that engages with viral phospholipids. Thus, besides the main Fab–peptide interaction, molecular recognition of MPER depends on semi-specific (electrostatic and hydrophobic) interactions with membranes and, reportedly, on specific binding to the phospholipid head groups. Here, based on available cryo-EM structures of Fab–Env complexes of the anti-MPER antibody 10E8, we sought to delineate the functional antibody–membrane interface using as the defining criterion the neutralization potency and binding affinity improvements induced by Arg substitutions. This rational, Arg-based mutagenesis strategy revealed the position-dependent contribution of electrostatic interactions upon inclusion of Arg-s at the CDR1, CDR2 or FR3 of the Fab light chain. Moreover, the contribution of the most effective Arg-s increased the potency enhancement induced by inclusion of a hydrophobic-at-interface Phe at position 100c of the heavy chain CDR3. In combination, the potency and affinity improvements by Arg residues delineated a protein–membrane interaction site, whose surface and position support a possible mechanism of action for 10E8-induced neutralization. Functional delineation of membrane-interacting patches could open new lines of research to optimize antibodies of therapeutic interest that target integral membrane epitopes. | Versión del editor: | https://doi.org/10.3390/ijms231810767 | URI: | http://hdl.handle.net/10261/296401 | DOI: | 10.3390/ijms231810767 | ISSN: | 1661-6596 | E-ISSN: | 1422-0067 |
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