Abstract
The hemagglutinin (HA) glycoproteins of influenza viruses play a key role in binding host cell receptors and in mediating virus-host cell membrane fusion during virus infection. Upon virus entry, HA is triggered by low pH and undergoes large structural rearrangements from a prefusion state to a postfusion state. While structures of prefusion state and postfusion state of HA have been reported, the intermediate structures remain elusive. Here, we report two distinct low pH intermediate conformations of the influenza virus HA using cryo-electron microscopy (cryo-EM). Our results show that a decrease in pH from 7.8 to 5.2 triggers the release of fusion peptides from the binding pockets and then causes a dramatic conformational change in the central helices, in which the membrane-proximal ends of the central helices unwind to an extended form. Accompanying the conformational changes of the central helices, the stem region of the HA undergoes an anticlockwise rotation of 9.5 degrees and a shift of 15 Å. The HA head, after being stabilized by an antibody, remains unchanged compared to the neutral pH state. Thus, the conformational change of the HA stem region observed in our research is likely to be independent of the HA head. These results provide new insights into the structural transition of HA during virus entry.
Highlights
HA is a transmembrane viral surface protein which is responsible for interacting with host cell receptors and mediating virus entry
In endosomes of the host cells, HA is triggered by low pH and undergoes a series of conformational change which is a conserved but highly dynamic process
The influenza virus hemagglutinin (HA) glycoprotein is synthesized as a ~560 amino acid precursor protein (HA0) of a single polypeptide chain, which is cleaved into the HA1 and HA2 subunits linked by a disulfide bond, either in the cell during virus assembly or on the cell surface during virus entry by host cell proteases[1,2]
Summary
The influenza virus hemagglutinin (HA) glycoprotein is synthesized as a ~560 amino acid precursor protein (HA0) of a single polypeptide chain, which is cleaved into the HA1 and HA2 subunits linked by a disulfide bond, either in the cell during virus assembly or on the cell surface during virus entry by host cell proteases[1,2]. The head encompasses the sialic acid receptor binding domains (RBDs), while the stem has a hydrophobic fusion peptide at the N-terminus and the transmembrane helix at the C-terminus of each HA2. Structures of the prefusion HA before or after protease cleavage and the six-helix bundle structure of the postfusion HA2 trimer provide insights into the initial and final stages of HA during virus entry [5,6,7,8], respectively. Molecular snapshots of HA in the intermediate states of the pre-postfusion transition, which are important for the development of universal antiviral drugs and vaccines, remain to be elucidated
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