Publication date: Jun 24, 2025

Coronaviruses use the spike protein (spike) to bind to target cells, and fuse the viral envelope with a host lipid membrane. Spike is a large trimeric surface glycoprotein, anchored to the viral membrane (envelope) by a single membrane-spanning polypeptide helix and a short intra-virion domain. In the SARS-CoV-2 virus, the spike is formed by three protomers of 1273 residues, each with two distinct domains separable by enzymatic proteolysis prior to infection. Thus far, enveloped virus surface glycoprotein structures have provided a detailed molecular view of the pre-fusion state, while structures of the post-fusion state have remained incomplete. The determination of the full-length structure of the SARS-CoV-2 spike in the post-fusion state is a landmark in furthering our understanding of the structural pre-requisites for membrane fusion. This perspective analyzes the fusion domain as revealed by the recent structure in the context of conserved sequences across diverse coronaviruses. We highlight the characterization of the membrane-embedded fusion peptide in a helical hairpin topology. This structure is discussed as a re-imagination of the helical hairpin hypothesis for polypeptide insertion into membranes, postulated by Engleman and Steitz over four decades ago.

Semantics

Original Article