Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface
The mechanism by which the HIV-1 MPER epitope is recognized by the potent neutralizing antibody 10E8 at membrane interfaces remains poorly understood. To solve this problem, we have optimized a 10E8 peptide epitope and analyzed the structure and binding activities of the antibody in membrane and mem...
| Autores: | ; ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Universidad del País Vasco |
| Repositorio: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/68854 |
| Acceso en línea: | http://hdl.handle.net/10810/68854 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | HIV-1, MPER, Structure, Membrane, Antibody HIV-1 MPER structure membrane antibody |
| _version_ | 1878729525435564032 |
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| author | Rujas Díez, Edurne |
| author2 | Caaveiro, Jose M.M. Partida Hanon, Angélica Gulzar, Naveed Morante, Koldo Apellaniz Unzalu, Beatriz García Porras, Miguel Bruix, Marta Tsumoto, Kouhei Scott, Jamie K. Jiménez, María Ángeles Nieva Escandón, José Luis |
| author2_role | author author author author author author author author author author author |
| author_browse | Apellaniz Unzalu, Beatriz Bruix, Marta Caaveiro, Jose M.M. García Porras, Miguel Gulzar, Naveed Jiménez, María Ángeles Morante, Koldo Nieva Escandón, José Luis Partida Hanon, Angélica Rujas Díez, Edurne Scott, Jamie K. Tsumoto, Kouhei |
| author_facet | Rujas Díez, Edurne Caaveiro, Jose M.M. Partida Hanon, Angélica Gulzar, Naveed Morante, Koldo Apellaniz Unzalu, Beatriz García Porras, Miguel Bruix, Marta Tsumoto, Kouhei Scott, Jamie K. Jiménez, María Ángeles Nieva Escandón, José Luis |
| author_role | author |
| collection | Addi. Archivo Digital para la Docencia y la Investigación |
| description | The mechanism by which the HIV-1 MPER epitope is recognized by the potent neutralizing antibody 10E8 at membrane interfaces remains poorly understood. To solve this problem, we have optimized a 10E8 peptide epitope and analyzed the structure and binding activities of the antibody in membrane and membrane-like environments. The X-ray crystal structure of the Fab-peptide complex in detergents revealed for the first time that the epitope of 10E8 comprises a continuous helix spanning the gp41 MPER/transmembrane domain junction (MPER-N-TMD; Env residues 671–687). The MPER-N-TMD helix projects beyond the tip of the heavy-chain complementarity determining region 3 loop, indicating that the antibody sits parallel to the plane of the membrane in binding the native epitope. Biophysical, biochemical and mutational analyses demonstrated that strengthening the affinity of 10E8 for the TMD helix in a membrane environment, correlated with its neutralizing potency. Our research clarifies the molecular mechanisms underlying broad neutralization of HIV-1 by 10E8, and the structure of its natural epitope. The conclusions of our research will guide future vaccine-design strategies targeting MPER. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_09abf12b18a473cbac4e8e94cb3aab38 |
| institution | Universidad del País Vasco |
| instname_str | Universidad del País Vasco |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:addi.ehu.eus:10810/68854 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | Springer Nature |
| publisherStr | Springer Nature |
| reponame_str | Addi. Archivo Digital para la Docencia y la Investigación |
| spelling | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface Rujas Díez, Edurne Caaveiro, Jose M.M. Partida Hanon, Angélica Gulzar, Naveed Morante, Koldo Apellaniz Unzalu, Beatriz García Porras, Miguel Bruix, Marta Tsumoto, Kouhei Scott, Jamie K. Jiménez, María Ángeles Nieva Escandón, José Luis HIV-1, MPER, Structure, Membrane, Antibody HIV-1 MPER structure membrane antibody The mechanism by which the HIV-1 MPER epitope is recognized by the potent neutralizing antibody 10E8 at membrane interfaces remains poorly understood. To solve this problem, we have optimized a 10E8 peptide epitope and analyzed the structure and binding activities of the antibody in membrane and membrane-like environments. The X-ray crystal structure of the Fab-peptide complex in detergents revealed for the first time that the epitope of 10E8 comprises a continuous helix spanning the gp41 MPER/transmembrane domain junction (MPER-N-TMD; Env residues 671–687). The MPER-N-TMD helix projects beyond the tip of the heavy-chain complementarity determining region 3 loop, indicating that the antibody sits parallel to the plane of the membrane in binding the native epitope. Biophysical, biochemical and mutational analyses demonstrated that strengthening the affinity of 10E8 for the TMD helix in a membrane environment, correlated with its neutralizing potency. Our research clarifies the molecular mechanisms underlying broad neutralization of HIV-1 by 10E8, and the structure of its natural epitope. The conclusions of our research will guide future vaccine-design strategies targeting MPER. This work was supported by NIH (grant number AI097051 to J.K.S. and J.L.N.), the Spanish Ministry of Economy (grant number CTQ2014-52633-P to M.B. and MA.J.) and the Basque Government (grant IT838-13 to J.L.N.). J.K.S. was supported by a Canada Research Chair. Work in the laboratory of K.T. was supported by JSPS KAKENHI-A grants 25249115 and 16H02420 (to K.T.), by the Platform for Drug Discovery, Informatics and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a JSPS KAKENHI-C grant 15K06962 (to J.M.M.C.). E.R. is recipient of a predoctoral fellowship from the Basque Government. A.P.-H. is recipient of a predoctoral fellowship 579971 from CONACYT. We thank Jean-Philippe Julien for helpful comments during preparation of the manuscript. Access to beamline AR-NW12 was granted by the Photon Factory Advisory Committee (Proposal 2014G190). Springer Nature http://hdl.handle.net/10810/68854 |
| spellingShingle | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface Rujas Díez, Edurne HIV-1, MPER, Structure, Membrane, Antibody HIV-1 MPER structure membrane antibody |
| title | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface |
| title_full | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface |
| title_fullStr | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface |
| title_full_unstemmed | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface |
| title_short | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface |
| title_sort | Structural basis for broad neutralization of HIV-1 through the molecular recognition of 10E8 helical epitope at the membrane interface |
| topic | HIV-1, MPER, Structure, Membrane, Antibody HIV-1 MPER structure membrane antibody |
| topic_facet | HIV-1, MPER, Structure, Membrane, Antibody HIV-1 MPER structure membrane antibody |
| url | http://hdl.handle.net/10810/68854 |