Ranaweera A, Ratnayake PU, Ekanayaka EAP, et al. Hydrogen-deuterium exchange supports independent membrane-interfacial fusion peptide and transmembrane domains in subunit 2 of influenza virus hemagglutinin protein, a structured and aqueous-protected. Biochemistry. 2019 Apr 22
The influenza virus hemagglutinin (HA) protein has HA1 and HA2 subunits, which form an initial complex. HA1´s bind host cell sialic acids which triggers endocytosis, HA1/HA2 separation, and HA2-mediated fusion between virus and endosome membranes. We report hydrogen-deuterium exchange-mass spectrometry(HDX-MS) on the HA2 subunit without HA1. HA2 contains fusion peptide(FP), soluble ectodomain(SE), transmembrane domain(TM) and endodomain. FP is a monomer by itself, while SE is a trimer-of-hairpins that includes an interior bundle of residue 38-105 helices, turns, and 154-178 strands packed antiparallel to the bundle. FP and TM extend from the same side of the SE hairpin, and fusion models often depict a FP/TM complex with membrane traversal of both domains that is important for membrane pore expansion. The HDX-MS data of the present study do not support this complex, and instead support independent FP and TM with respective membrane interfacial and traversal locations. The data also show low aqueous exposure of the 22-38 segment, consistent with retention of the 23-35 antiparallel β sheet observed in the initial HA1/HA2 complex. We propose the β sheet as a semi-rigid connector between FP and SE that enables close membrane apposition prior to fusion. The I173E mutant exhibits greater exchange for 22-69 and 150-191, consistent with dissociation of SE C-terminal strands from interior N-helices. Similar trends are observed for G1E mutant, as well as lower exchange for G1E FP. Fusion is highly-impaired with either mutant, which correlates with reduced membrane apposition, and for G1E, FP binding to SE rather than target membrane.
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