TMPRSS2 and glycan receptors synergistically facilitate coronavirus entry

Haofeng Wang; Xiaoce Liu; Xiang Zhang; Zhuoqian Zhao; Yuchi Lu; Dingzhe Pu; Zeyang Zhang; Jie Chen; Yajie Wang; Mengfei Li; Xuxue Dong; Yinkai Duan; Yujia He; Qiyu Mao; Hangtian Guo; Haoran Sun; Yihan Zhou; Qi Yang; Yan Gao; Xiuna Yang; Hongzhi Cao; Luke Guddat; Lei Sun; Zihe Rao; Haitao Yang

doi:10.1016/j.cell.2024.06.016

TMPRSS2 and glycan receptors synergistically facilitate coronavirus entry

Cell. 2024 Aug 8;187(16):4261-4271.e17. doi: 10.1016/j.cell.2024.06.016. Epub 2024 Jul 3.

Authors

Haofeng Wang¹, Xiaoce Liu¹, Xiang Zhang², Zhuoqian Zhao³, Yuchi Lu³, Dingzhe Pu⁴, Zeyang Zhang³, Jie Chen¹, Yajie Wang², Mengfei Li¹, Xuxue Dong⁴, Yinkai Duan¹, Yujia He¹, Qiyu Mao², Hangtian Guo⁵, Haoran Sun¹, Yihan Zhou¹, Qi Yang⁶, Yan Gao¹, Xiuna Yang¹, Hongzhi Cao⁷, Luke Guddat⁸, Lei Sun⁹, Zihe Rao¹⁰, Haitao Yang¹¹

Affiliations

¹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China.
² Shanghai Fifth People's Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Medical Epigenetics and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
³ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; Lingang Laboratory, Shanghai 200031, China.
⁴ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; Guangzhou Laboratory, Guangzhou 510005, China.
⁵ The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
⁶ Guangzhou Laboratory, Guangzhou 510005, China.
⁷ Key Laboratory of Marine Drugs of Ministry of Education, Shandong Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
⁸ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
⁹ Shanghai Fifth People's Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Medical Epigenetics and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: llsun@fudan.edu.cn.
¹⁰ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China; Shanghai Fifth People's Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Key Laboratory of Medical Epigenetics and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin 300353, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: raozh@tsinghua.edu.cn.
¹¹ Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Shanghai Clinical Research and Trial Center, Shanghai 201210, China. Electronic address: yanght@shanghaitech.edu.cn.

PMID: 38964329
DOI: 10.1016/j.cell.2024.06.016

Abstract

The entry of coronaviruses is initiated by spike recognition of host cellular receptors, involving proteinaceous and/or glycan receptors. Recently, TMPRSS2 was identified as the proteinaceous receptor for HCoV-HKU1 alongside sialoglycan as a glycan receptor. However, the underlying mechanisms for viral entry remain unknown. Here, we investigated the HCoV-HKU1C spike in the inactive, glycan-activated, and functionally anchored states, revealing that sialoglycan binding induces a conformational change of the NTD and promotes the neighboring RBD of the spike to open for TMPRSS2 recognition, exhibiting a synergistic mechanism for the entry of HCoV-HKU1. The RBD of HCoV-HKU1 features an insertion subdomain that recognizes TMPRSS2 through three previously undiscovered interfaces. Furthermore, structural investigation of HCoV-HKU1A in combination with mutagenesis and binding assays confirms a conserved receptor recognition pattern adopted by HCoV-HKU1. These studies advance our understanding of the complex viral-host interactions during entry, laying the groundwork for developing new therapeutics against coronavirus-associated diseases.

Keywords: HCoV-HKU1; TMPRSS2; glycan receptor; proteinaceous receptor; viral entry.

MeSH terms

Coronavirus / metabolism
HEK293 Cells
Humans
Models, Molecular
Polysaccharides / chemistry
Polysaccharides / metabolism
Protein Binding
Receptors, Virus / chemistry
Receptors, Virus / metabolism
Serine Endopeptidases* / metabolism
Spike Glycoprotein, Coronavirus* / chemistry
Spike Glycoprotein, Coronavirus* / metabolism
Virus Internalization*

Substances

TMPRSS2 protein, human
Serine Endopeptidases
Spike Glycoprotein, Coronavirus
Polysaccharides
Receptors, Virus