8y88
Structure of HCoV-HKU1C spike in the functionally anchored-2up conformation with 2TMPRSS2
Structural highlights
FunctionSPIKE_CVHN5 S1 attaches the virion to the cell membrane by interacting with cell receptors, initiating the infection. S2 is a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Presumably interacts with target cell lipid raft after cell attachment (By similarity). Publication Abstract from PubMedThe 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. TMPRSS2 and glycan receptors synergistically facilitate coronavirus entry.,Wang H, Liu X, Zhang X, Zhao Z, Lu Y, Pu D, Zhang Z, Chen J, Wang Y, Li M, Dong X, Duan Y, He Y, Mao Q, Guo H, Sun H, Zhou Y, Yang Q, Gao Y, Yang X, Cao H, Guddat L, Sun L, Rao Z, Yang H Cell. 2024 Jun 21:S0092-8674(24)00656-1. doi: 10.1016/j.cell.2024.06.016. PMID:38964329[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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