Abstract
Influenza hemagglutinin (HA) is a viral membrane bound protein that plays a critical role in the viral life cycle by mediating entry into target cells. HA exploits the lowering of the pH in the endosomal compartment to initiate a series of conformational changes that promote access of the viral genetic material to the cytoplasm, and hence viral replication. In this review we will first discuss what is known about the structural properties of HA as a function of pH. Next, we will discuss the dynamics and intermediate states of HA. We will then discuss the specific residues that are thought to be titrated by the change in pH and possible mechanisms for the pH triggered conformational changes. Finally, we will discuss small molecules that disrupt the pH trigger and thus serve as potential therapeutic strategies to prevent influenza infection.
Highlights
It has long been appreciated that protein structures are adapted to the pH of their environment
HA plays a critical role in influenza infection and it is a potential target for therapeutic interventions
In the case of small molecule inhibitors TBHQ and Arbidol, they bind to the neutral conformation of Group 2 HA (e.g., H3 and H7 HA) in close proximity to the stem loop (Figure 4A) and they have been shown to disrupt the transition to the low pH form by stabilization of the neutral pH form (Russell et al, 2008; Antanasijevic et al, 2013; Kadam and Wilson, 2017)
Summary
It has long been appreciated that protein structures are adapted to the pH of their environment. In this review we will discuss the pH related properties of influenza hemagglutinin (HA), a viral protein that has adapted to exploit the change from neutral pH (in the extracellular fluid) to pH ∼5 (in the endosome of target cells) for the purpose of allowing the viral genetic material access to the cytoplasm (White et al, 1982). The importance of pH to HA function and the model for a pH induced conformational change are strongly supported
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