Functional Delineation of a Protein–Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8
dc.bibliographicCitation.firstPage | 10767 | |
dc.bibliographicCitation.issue | 18 | |
dc.bibliographicCitation.journalTitle | International journal of molecular sciences | eng |
dc.bibliographicCitation.volume | 23 | |
dc.contributor.author | Insausti, Sara | |
dc.contributor.author | Garcia-Porras, Miguel | |
dc.contributor.author | Torralba, Johana | |
dc.contributor.author | Morillo, Izaskun | |
dc.contributor.author | Ramos-Caballero, Ander | |
dc.contributor.author | de la Arada, Igor | |
dc.contributor.author | Apellaniz, Beatriz | |
dc.contributor.author | Caaveiro, Jose M. M. | |
dc.contributor.author | Carravilla, Pablo | |
dc.contributor.author | Eggeling, Christian | |
dc.contributor.author | Rujas, Edurne | |
dc.contributor.author | Nieva, Jose L. | |
dc.date.accessioned | 2023-02-06T07:28:18Z | |
dc.date.available | 2023-02-06T07:28:18Z | |
dc.date.issued | 2022 | |
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. | eng |
dc.description.version | publishedVersion | eng |
dc.identifier.uri | https://oa.tib.eu/renate/handle/123456789/11242 | |
dc.identifier.uri | http://dx.doi.org/10.34657/10278 | |
dc.language.iso | eng | |
dc.publisher | Basel : Molecular Diversity Preservation International (MDPI) | |
dc.relation.doi | https://doi.org/10.3390/ijms231810767 | |
dc.relation.essn | 1422-0067 | |
dc.relation.essn | 1661-6596 | |
dc.rights.license | CC BY 4.0 Unported | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject.ddc | 570 | |
dc.subject.ddc | 540 | |
dc.subject.other | anti-MPER HIV antibody | eng |
dc.subject.other | antibody–membrane interactions | eng |
dc.subject.other | broadly neutralizing antibody 10E8 | eng |
dc.subject.other | HIV neutralization | eng |
dc.subject.other | MPER epitope recognition | eng |
dc.subject.other | protein–membrane interactions | eng |
dc.title | Functional Delineation of a Protein–Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E8 | eng |
dc.type | Article | eng |
dc.type | Text | eng |
tib.accessRights | openAccess | |
wgl.contributor | IPHT | |
wgl.subject | Biowissenschaften/Biologie | ger |
wgl.subject | Chemie | ger |
wgl.type | Zeitschriftenartikel | ger |
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