Functional Delineation of a Protein–Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8
dc.contributor.author | Insausti González, Sara | |
dc.contributor.author | García Porras, Miguel | |
dc.contributor.author | Torralba Iturbe, Johana | |
dc.contributor.author | Morillo Melero, Izaskun | |
dc.contributor.author | Ramos Caballero, Ander | |
dc.contributor.author | De la Arada Echevarría, Igor | |
dc.contributor.author | Apellaniz Unzalu, Beatriz | |
dc.contributor.author | Caaveiro, Jose M.M. | |
dc.contributor.author | Carravilla Palomanes, Pablo | |
dc.contributor.author | Eggeling, Christian | |
dc.contributor.author | Rujas Díez, Edurne | |
dc.contributor.author | Nieva Escandón, José Luis | |
dc.date.accessioned | 2022-09-30T13:53:54Z | |
dc.date.available | 2022-09-30T13:53:54Z | |
dc.date.issued | 2022-09-15 | |
dc.identifier.citation | International Journal of Molecular Sciences 23(18) : (2022) // Article ID 10767 | es_ES |
dc.identifier.issn | 1422-0067 | |
dc.identifier.uri | http://hdl.handle.net/10810/57886 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | This study was supported by the Spanish MCIN (Grants PID2021-126014OB-I00 MCIN/AEI/FEDER, UE to JLN and BA; and PID2021-122212OA-I00 MCIN/AEI/FEDER, UE to ER), Basque Government (Grant: IT1449-22) and JSPS KAKENHI 20H03228 (to J.M.M.C.). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | MDPI | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2021-126014OB-I00 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2021-122212OA-I00 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | MPER epitope recognition | es_ES |
dc.subject | protein–membrane interactions | es_ES |
dc.subject | antibody–membrane interactions | es_ES |
dc.subject | anti-MPER HIV antibody | es_ES |
dc.subject | HIV neutralization | es_ES |
dc.subject | broadly neutralizing antibody 10E8 | es_ES |
dc.title | Functional Delineation of a Protein–Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8 | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.date.updated | 2022-09-22T12:04:50Z | |
dc.rights.holder | © 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/). | es_ES |
dc.relation.publisherversion | https://www.mdpi.com/1422-0067/23/18/10767 | es_ES |
dc.identifier.doi | 10.3390/ijms231810767 | |
dc.departamentoes | Bioquímica y biología molecular | |
dc.departamentoes | Farmacia y ciencias de los alimentos | |
dc.departamentoeu | Biokimika eta biologia molekularra | |
dc.departamentoeu | Farmazia eta elikagaien zientziak |
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Except where otherwise noted, this item's license is described as © 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).