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Human coronavirus HKU1 spike structures reveal the basis for sialoglycan specificity and carbohydrate-promoted conformational changes

Author

Listed:
  • Min Jin

    (University of Toronto)

  • Zaky Hassan

    (University of Toronto)

  • Zhijie Li

    (University of Toronto)

  • Ying Liu

    (University of Toronto)

  • Aleksandra Marakhovskaia

    (University of Toronto)

  • Alan H. M. Wong

    (University of Toronto)

  • Adam Forman

    (University of Toronto)

  • Mark Nitz

    (University of Toronto)

  • Michel Gilbert

    (National Research Council Canada)

  • Hai Yu

    (University of California-Davis)

  • Xi Chen

    (University of California-Davis)

  • James M. Rini

    (University of Toronto
    University of Toronto)

Abstract

The human coronavirus HKU1 uses both sialoglycoconjugates and the protein transmembrane serine protease 2 (TMPRSS2) as receptors. Carbohydrate binding leads to the spike protein up conformation required for TMPRSS2 binding, an outcome suggesting a distinct mechanism for driving fusion of the viral and host cell membranes. Nevertheless, the conformational changes promoted by carbohydrate binding have not been fully elucidated and the basis for HKU1’s carbohydrate binding specificity remains unknown. Reported here are high resolution cryo-EM structures of the HKU1 spike protein trimer in its apo form and in complex with the carbohydrate moiety of a candidate carbohydrate receptor, the 9-O-acetylated GD3 ganglioside. The structures show that the spike monomer can exist in four discrete conformational states and that progression through them would promote the up conformation upon carbohydrate binding. We also show that a six-amino-acid insert is a determinant of HKU1’s specificity for gangliosides containing a 9-O-acetylated α2–8-linked disialic acid moiety and that HKU1 shows weak affinity for the 9-O-acetylated sialic acids found on decoy receptors such as mucins.

Suggested Citation

  • Min Jin & Zaky Hassan & Zhijie Li & Ying Liu & Aleksandra Marakhovskaia & Alan H. M. Wong & Adam Forman & Mark Nitz & Michel Gilbert & Hai Yu & Xi Chen & James M. Rini, 2025. "Human coronavirus HKU1 spike structures reveal the basis for sialoglycan specificity and carbohydrate-promoted conformational changes," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59137-y
    DOI: 10.1038/s41467-025-59137-y
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