Human coronavirus HKU1 recognition of the TMPRSS2 host receptor
The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. Here, we designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2 providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among human type 2 transmembrane serine proteases. We found that human, rat, hamster and camel TMPRSS2 promote HKU1 S-mediated entry into cells and identified key residues governing host receptor usage. Our data show that serum antibodies targeting the HKU1 RBD TMPRSS2 binding-site are key for neutralization and that HKU1 uses conformational masking and glycan shielding to balance immune evasion and receptor engagement.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 09. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
McCallum, Matthew [VerfasserIn] |
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| Anmerkungen: |
Date Revised 10.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2024.01.09.574565 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367510081 |
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| 520 | |a The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. Here, we designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2 providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among human type 2 transmembrane serine proteases. We found that human, rat, hamster and camel TMPRSS2 promote HKU1 S-mediated entry into cells and identified key residues governing host receptor usage. Our data show that serum antibodies targeting the HKU1 RBD TMPRSS2 binding-site are key for neutralization and that HKU1 uses conformational masking and glycan shielding to balance immune evasion and receptor engagement | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Park, Young-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Stewart, Cameron |e verfasserin |4 aut | |
| 700 | 1 | |a Sprouse, Kaitlin R |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Jack |e verfasserin |4 aut | |
| 700 | 1 | |a Tortorici, M Alejandra |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, Cecily |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Emily |e verfasserin |4 aut | |
| 700 | 1 | |a Ieven, Margareta |e verfasserin |4 aut | |
| 700 | 1 | |a Telenti, Amalio |e verfasserin |4 aut | |
| 700 | 1 | |a Veesler, David |e verfasserin |4 aut | |
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