Structural basis for the recognition of HCoV-HKU1 by human TMPRSS2

Abstract

Human coronaviruses are pathogens capable of causing respiratory illnesses in humans, with seven identified species, 1 three of which have caused epidemics or global pandemics in the past two decades, namely, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), 2 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), 3 and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). 4 Along with these three viruses, HCoV-HKU1 (HKU1) belongs to the β-coronavirus genus. With three serotypes (HKU1-A, HKU1-B, and HKU1-C), HKU1 infection commonly causes the common cold, but also leads to severe lower respiratory tract infections. 5 The spike (S) protein of HKU1 plays a crucial role in cell invasion by binding to host receptors, with the transmembrane serine protease TMPRSS2 recently identified as its protein receptor. 6 TMPRSS2 comprises intracellular, transmembrane, LDL receptor A (LDLR-A, residues 112–149), scavenger receptor cysteine-rich (SRCR, residues 150–242), and C-terminal serine protease (SP, residues 256–489) domains. However, the structural basis of TMPRSS2 interaction with the S protein remains elusive. Here we present the cryo-electron microscopy (cryo-EM) structures of the HKU1-B S protein in the apo or receptor-bound states. The S protein of HKU1-B exhibits multiple conformations in the apo state, including a closed conformation and two active conformations. In the active conformations, one or two receptor-binding domains (RBD) of the S protein are in “up” position. Binding of the receptor TMPRSS2 results in more open conformations of the S protein, changing the interaction network in the S protein and triggering a trend towards the post-fusion state, thus facilitating the initiation of the invasion into host cells. Our research enhances the understanding of the HKU1 infection process, providing crucial insights for the development and optimization of vaccines and therapeutic interventions.

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