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University of Washington

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Cell, Available online 3 July 2024 | https://doi.org/10.1016/j.cell.2024.06.006 Human coronavirus HKU1 recognition of the TMPRSS2 host receptor

Matthew McCallum ^1,5, Young-Jun Park ^1,2,5, Cameron Stewart¹, Kaitlin R. Sprouse ^1,2, Amin Addetia¹, Jack Brown¹, M. Alejandra Tortorici ¹, Cecily Gibson^1,2, Emily Wong³, Margareta Ieven⁴, Amalio Telenti³, David Veesler^1,2,6

¹Department of Biochemistry, University of Washington, Seattle, WA, USA

²Howard Hughes Medical Institute, Seattle, WA 98195, USA

³Vir Biotechnology, San Francisco, CA 94158, USA

⁴Laboratory of Clinical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium

⁵These authors contributed equally

⁶Lead contact

Corresponding author : David Veesler

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. 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 orthologous proteases. We identified TMPRSS2 orthologs from five mammalian orders promoting HKU1 S-mediated entry into cells along with key residues governing host receptor usage. Our data show that the TMPRSS2 binding motif is a site of vulnerability to neutralizing antibodies and suggest that HKU1 uses S conformational masking and glycan shielding to balance immune evasion and receptor engagement.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-09)
연구진국외 연구진
분야 의약학 > 면역의학

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