Investigation of the pH Induced Conformational Rearrangement of Influenza Hemagglutinin

Lin, Xinrong; Noel, Jeffrey K.; Eddy, Nathanial R.; Ma, Jianpeng; Onuchic, José N.

doi:10.1016/j.bpj.2015.11.126

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“…Recently, simulation-based studies have suggested that the folding of the B-loop into the extended coiled coil is not a downhill process and that only the folding of the first half of S2 is energetically favorable. [7][8][9] This result supports a different mechanism. In this mechanism, the FPs are released from the core of the trimer upon acidification.…”

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confidence: 65%

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Stability of HA2 Prefusion Structure and pH-Induced Conformational Changes in the HA2 Domain of H3N2 Hemagglutinin

2021

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Influenza hemagglutinin is the fusion protein that mediates fusion of the viral and host membranes through a large conformational change upon acidification in the developing endosome. The "spring-loaded" model has long been used to describe the mechanism of hemagglutinin and other type 1 viral glycoproteins. This model postulates a metastable conformation of the HA2 subunit, caged from adopting a lower-free energy conformation by the HA1 subunit. Here, using a combination of biochemical and spectroscopic methods, we study a truncated construct of HA2 (HA2*, lacking the transmembrane domain) recombinantly expressed in Escherichia coli as a model for HA2 without the influence of HA1. Our data show that HA2* folds into a conformation like that of HA2 in full length HA and forms trimers. Upon acidification, HA2* undergoes a conformational change that is consistent with the change from pre-to postfusion HA2 in HA. This conformational change is fast and occurs on a time scale that is not consistent with aggregation. These results suggest that the prefusion conformation of HA2 is stable and the change to the postfusion conformation is due to protonation of HA2 itself and not merely uncaging by HA1.

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confidence: 65%

“…A higher absorbance means a larger amount of HRP present. At neutral pH (7), the + wells have a higher average absorbance than the − wells, suggesting binding of CR8020 to HA2* beyond nonspecific interactions.…”

Section: Antibody Bindingmentioning

confidence: 99%