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: |
|
|---|
Preprint| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 12. Jan. Zur Gesamtaufnahme - year:2024 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
McCallum, Matthew [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2024.01.09.574565 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI042124840 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI042124840 | ||
| 003 | DE-627 | ||
| 005 | 20240113124900.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240111s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2024.01.09.574565 |2 doi | |
| 035 | |a (DE-627)XBI042124840 | ||
| 035 | |a (biorXiv)10.1101/2024.01.09.574565 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a McCallum, Matthew |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Human coronavirus HKU1 recognition of the TMPRSS2 host receptor |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 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 Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Park, Young-Jun |4 aut | |
| 700 | 1 | |a Stewart, Cameron |4 aut | |
| 700 | 1 | |a Sprouse, Kaitlin R. |4 aut | |
| 700 | 1 | |a Brown, Jack |4 aut | |
| 700 | 1 | |a Tortorici, M. Alejandra |4 aut | |
| 700 | 1 | |a Gibson, Cecily |4 aut | |
| 700 | 1 | |a Wong, Emily |4 aut | |
| 700 | 1 | |a Ieven, Margareta |4 aut | |
| 700 | 1 | |a Telenti, Amalio |4 aut | |
| 700 | 1 | |a Veesler, David |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2024) vom: 12. Jan. |
| 773 | 1 | 8 | |g year:2024 |g day:12 |g month:01 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2024.01.09.574565 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 12 |c 01 | ||