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X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications
The retroviral envelope-derived proteins syncytin-1 and syncytin-2 (syn1 and syn2) drive placentation in humans by forming a syncytiotophoblast, a structure allowing for an exchange interface between maternal and fetal blood during pregnancy. Despite their essential role, little is known about the m...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Author(s). Published by Elsevier Ltd.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094397/ https://www.ncbi.nlm.nih.gov/pubmed/31711961 http://dx.doi.org/10.1016/j.jmb.2019.10.020 |
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author | Ruigrok, Katinka Vaney, Marie-Christine Buchrieser, Julian Baquero, Eduard Hellert, Jan Baron, Bruno England, Patrick Schwartz, Olivier Rey, Felix A. Backovic, Marija |
author_facet | Ruigrok, Katinka Vaney, Marie-Christine Buchrieser, Julian Baquero, Eduard Hellert, Jan Baron, Bruno England, Patrick Schwartz, Olivier Rey, Felix A. Backovic, Marija |
author_sort | Ruigrok, Katinka |
collection | PubMed |
description | The retroviral envelope-derived proteins syncytin-1 and syncytin-2 (syn1 and syn2) drive placentation in humans by forming a syncytiotophoblast, a structure allowing for an exchange interface between maternal and fetal blood during pregnancy. Despite their essential role, little is known about the molecular mechanism underlying the syncytins' function. We report here the X-ray structures of the syn1 and syn2 transmembrane subunit ectodomains, featuring a 6-helix bundle (6HB) typical of the post-fusion state of gamma-retrovirus and filovirus fusion proteins. Contrary to the filoviruses, for which the fusion glycoprotein was crystallized both in the post-fusion and in the spring-loaded pre-fusion form, the highly unstable nature of the syncytins' prefusion form has precluded structural studies. We undertook a proline-scanning approach searching for regions in the syn1 6HB central helix that tolerate the introduction of helix-breaker residues and still fold correctly in the pre-fusion form. We found that there is indeed such a region, located two α-helical turns downstream a stutter in the central coiled-coil helix - precisely where the breaks of the spring-loaded helix of the filoviruses map. These mutants were fusion-inactive as they cannot form the 6HB, similar to the “SOSIP” mutant of HIV Env that allowed the high-resolution structural characterization of its labile pre-fusion form. These results now open a new window of opportunity to engineer more stable variants of the elusive pre-fusion trimer of the syncytins and other gamma-retroviruses envelope proteins for structural characterization. |
format | Online Article Text |
id | pubmed-7094397 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The Author(s). Published by Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70943972020-03-25 X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications Ruigrok, Katinka Vaney, Marie-Christine Buchrieser, Julian Baquero, Eduard Hellert, Jan Baron, Bruno England, Patrick Schwartz, Olivier Rey, Felix A. Backovic, Marija J Mol Biol Article The retroviral envelope-derived proteins syncytin-1 and syncytin-2 (syn1 and syn2) drive placentation in humans by forming a syncytiotophoblast, a structure allowing for an exchange interface between maternal and fetal blood during pregnancy. Despite their essential role, little is known about the molecular mechanism underlying the syncytins' function. We report here the X-ray structures of the syn1 and syn2 transmembrane subunit ectodomains, featuring a 6-helix bundle (6HB) typical of the post-fusion state of gamma-retrovirus and filovirus fusion proteins. Contrary to the filoviruses, for which the fusion glycoprotein was crystallized both in the post-fusion and in the spring-loaded pre-fusion form, the highly unstable nature of the syncytins' prefusion form has precluded structural studies. We undertook a proline-scanning approach searching for regions in the syn1 6HB central helix that tolerate the introduction of helix-breaker residues and still fold correctly in the pre-fusion form. We found that there is indeed such a region, located two α-helical turns downstream a stutter in the central coiled-coil helix - precisely where the breaks of the spring-loaded helix of the filoviruses map. These mutants were fusion-inactive as they cannot form the 6HB, similar to the “SOSIP” mutant of HIV Env that allowed the high-resolution structural characterization of its labile pre-fusion form. These results now open a new window of opportunity to engineer more stable variants of the elusive pre-fusion trimer of the syncytins and other gamma-retroviruses envelope proteins for structural characterization. The Author(s). Published by Elsevier Ltd. 2019-12-06 2019-11-08 /pmc/articles/PMC7094397/ /pubmed/31711961 http://dx.doi.org/10.1016/j.jmb.2019.10.020 Text en © 2019 The Author(s) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Ruigrok, Katinka Vaney, Marie-Christine Buchrieser, Julian Baquero, Eduard Hellert, Jan Baron, Bruno England, Patrick Schwartz, Olivier Rey, Felix A. Backovic, Marija X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications |
title | X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications |
title_full | X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications |
title_fullStr | X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications |
title_full_unstemmed | X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications |
title_short | X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications |
title_sort | x-ray structures of the post-fusion 6-helix bundle of the human syncytins and their functional implications |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094397/ https://www.ncbi.nlm.nih.gov/pubmed/31711961 http://dx.doi.org/10.1016/j.jmb.2019.10.020 |
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