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Publication Abstract from PubMed

The hemagglutinin (HA) envelope protein of influenza virus mediates viral entry through membrane fusion in the acidic environment of the endosome. Crystal structures of HA in pre- and post-fusion states have laid the foundation for proposals for a general fusion mechanism for viral envelope proteins. The large-scale conformational rearrangement of HA at low pH is triggered by a loop-to-helix transition of an inter-helical loop (B loop) within the fusion domain, and is often referred to as the "spring-loaded" mechanism. Although the receptor-binding HA1 subunit is believed to act as "clamp" to keep the B loop in its metastable pre-fusion state at neutral pH, the "pH sensors" that are responsible for the clamp release and the ensuing structural transitions have remained elusive. Here we identify a mutation in the HA2 fusion domain from the influenza H2 subtype that stabilizes the HA trimer in a prefusion-like state at and below fusogenic pH. Crystal structures of this putative early intermediate state reveal disruptions of ionic interactions at the HA1-HA2 interface at acidic pH and deformation of the HA1 membrane distal domain. Along with neutralization of glutamate residues on the B loop, these changes cause a rotation of the B loop and solvent exposure of conserved phenylalanines, which are key residues at the trimer interface of the post-fusion structure. Thus, our study reveals the possible initial structural event that leads to release of the B loop from its pre-fusion conformation, which is aided by unexpected structural changes within the membrane-distal HA1 domain at low pH.

Structural characterization of an early fusion intermediate of influenza virus hemagglutinin.,Xu R, Wilson IA J Virol. 2011 Mar 2. PMID:21367895^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.