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Studies on low pH-activated HA2 from Influenza haemagglutinin

Ogrodowicz, RW; (2017) Studies on low pH-activated HA2 from Influenza haemagglutinin. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Influenza A haemagglutinin is a surface glycoprotein of Influenza virus, responsible for the initial attachment of the virus to the target cell and, at a later stage, for viral membrane fusion. At the acidic pH of the endosome, the HA molecule undergoes an irreversible structural rearrangement. In consequence, the hydrophobic terminal segments of HA2 are moved to the same end of the refolded molecule, promoting membrane fusion. 16 haemagglutinin subtypes (H1-H16) identified to date can be divided into two groups based on characteristic structural features. The low pH-induced structures of proteolytically prepared and E.coli-expressed fragments of influenza A H3 HA2 (group 2 HA) were previously determined by X-ray crystallography. This study presents structures of proteolytically prepared and recombinantly- expressed fragments of H1 HA2 in a postfusion conformation. Refolded H1 HA2, belonging to group 1 HA, adopts a hairpin-like conformation, similar to that of a rearranged H3 HA2. Structures were compared to the known structures of low pH-activated HA2, to gain a better understanding of the structural differences between the two groups of HA. The data show the structures of the refolded HA2 to be conserved between the HA groups with minor differences. These structural data are supplemented with functional studies involving the cross-reactive FI6 antibody. FI6 antibody binds near the conserved fusion subdomain of the HA molecule and thus interferes with the low pH-triggered conformational change of HA. Additional methods employed in this study, such as limited proteolysis, electron microscopy, biolayer interferometry and MDCK1 cell infection, give insight into the mechanism of FI6 antibody-mediated neutralization, and highlight the differences in infectivity of H1N1 and H3N2 viruses neutralized by the FI6 antibody.

Type: Thesis (Doctoral)
Title: Studies on low pH-activated HA2 from Influenza haemagglutinin
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1540872
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