Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein
SARS-CoV-2 spike protein plays a key role in mediating viral entry and inducing host immune responses. It can adopt either an open or closed conformation based on the position of its receptor-binding domain (RBD). It is yet unclear what causes these conformational changes or how they influence the s...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/74060 |
| _version_ | 1797404880727441408 |
|---|---|
| author | Qibin Geng Yushun Wan Fu-Chun Hsueh Jian Shang Gang Ye Fan Bu Morgan Herbst Rowan Wilkens Bin Liu Fang Li |
| author_facet | Qibin Geng Yushun Wan Fu-Chun Hsueh Jian Shang Gang Ye Fan Bu Morgan Herbst Rowan Wilkens Bin Liu Fang Li |
| author_sort | Qibin Geng |
| collection | DOAJ |
| description | SARS-CoV-2 spike protein plays a key role in mediating viral entry and inducing host immune responses. It can adopt either an open or closed conformation based on the position of its receptor-binding domain (RBD). It is yet unclear what causes these conformational changes or how they influence the spike’s functions. Here, we show that Lys417 in the RBD plays dual roles in the spike’s structure: it stabilizes the closed conformation of the trimeric spike by mediating inter-spike–subunit interactions; it also directly interacts with ACE2 receptor. Hence, a K417V mutation has opposing effects on the spike’s function: it opens up the spike for better ACE2 binding while weakening the RBD’s direct binding to ACE2. The net outcomes of this mutation are to allow the spike to bind ACE2 with higher probability and mediate viral entry more efficiently, but become more exposed to neutralizing antibodies. Given that residue 417 has been a viral mutational hotspot, SARS-CoV-2 may have been evolving to strike a balance between infection potency and immune evasion, contributing to its pandemic spread. |
| first_indexed | 2024-03-09T03:01:28Z |
| format | Article |
| id | doaj.art-edb16a40cc674cd1a1f54b7d553de5ce |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-09T03:01:28Z |
| publishDate | 2023-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-edb16a40cc674cd1a1f54b7d553de5ce2023-12-04T15:28:26ZengeLife Sciences Publications LtdeLife2050-084X2023-11-011210.7554/eLife.74060Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike proteinQibin Geng0Yushun Wan1Fu-Chun Hsueh2Jian Shang3Gang Ye4https://orcid.org/0000-0001-6034-2174Fan Bu5Morgan Herbst6Rowan Wilkens7Bin Liu8https://orcid.org/0000-0002-6581-780XFang Li9https://orcid.org/0000-0002-1958-366XDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesHormel Institute, University of Minnesota, Austin, United StatesDepartment of Pharmacology, University of Minnesota Medical School, Minneapolis, United States; Center for Coronavirus Research, University of Minnesota, Minneapolis, United StatesSARS-CoV-2 spike protein plays a key role in mediating viral entry and inducing host immune responses. It can adopt either an open or closed conformation based on the position of its receptor-binding domain (RBD). It is yet unclear what causes these conformational changes or how they influence the spike’s functions. Here, we show that Lys417 in the RBD plays dual roles in the spike’s structure: it stabilizes the closed conformation of the trimeric spike by mediating inter-spike–subunit interactions; it also directly interacts with ACE2 receptor. Hence, a K417V mutation has opposing effects on the spike’s function: it opens up the spike for better ACE2 binding while weakening the RBD’s direct binding to ACE2. The net outcomes of this mutation are to allow the spike to bind ACE2 with higher probability and mediate viral entry more efficiently, but become more exposed to neutralizing antibodies. Given that residue 417 has been a viral mutational hotspot, SARS-CoV-2 may have been evolving to strike a balance between infection potency and immune evasion, contributing to its pandemic spread.https://elifesciences.org/articles/74060SARS-CoV-2spike proteinviral entryimmune evasivenessreceptor-binding domain |
| spellingShingle | Qibin Geng Yushun Wan Fu-Chun Hsueh Jian Shang Gang Ye Fan Bu Morgan Herbst Rowan Wilkens Bin Liu Fang Li Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein eLife SARS-CoV-2 spike protein viral entry immune evasiveness receptor-binding domain |
| title | Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein |
| title_full | Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein |
| title_fullStr | Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein |
| title_full_unstemmed | Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein |
| title_short | Lys417 acts as a molecular switch that regulates the conformation of SARS-CoV-2 spike protein |
| title_sort | lys417 acts as a molecular switch that regulates the conformation of sars cov 2 spike protein |
| topic | SARS-CoV-2 spike protein viral entry immune evasiveness receptor-binding domain |
| url | https://elifesciences.org/articles/74060 |
| work_keys_str_mv | AT qibingeng lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT yushunwan lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT fuchunhsueh lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT jianshang lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT gangye lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT fanbu lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT morganherbst lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT rowanwilkens lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT binliu lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein AT fangli lys417actsasamolecularswitchthatregulatestheconformationofsarscov2spikeprotein |