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Human coronavirus HKU1 recognition of the TMPRSS2 host receptor.


ABSTRACT: 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.

SUBMITTER: McCallum M 

PROVIDER: S-EPMC10802434 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Human coronavirus HKU1 recognition of the TMPRSS2 host receptor.

McCallum Matthew M   Park Young-Jun YJ   Stewart Cameron C   Sprouse Kaitlin R KR   Brown Jack J   Tortorici M Alejandra MA   Gibson Cecily C   Wong Emily E   Ieven Margareta M   Telenti Amalio A   Veesler David D  

bioRxiv : the preprint server for biology 20240109


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 provi  ...[more]

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