tetano
Editor, Senior Moderator
J Phys Chem B. 2016 Aug 19. [Epub ahead of print]
[h=1]Lowered pH Leads to Fusion Peptide Release and a Highly-Dynamic Intermediate of Influenza Hemagglutinin.[/h] Lin X, Noel JK, Wang Q, Ma J, Onuchic JN.
[h=3]Abstract[/h] Hemagglutinin (HA), the membrane-bound fusion protein of the Influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the dynamic consequences of the pH trigger, explicit-solvent molecular dynamics simulations were employed to investigate the initial stages of the HA transition. Our results indicate that lowered pH destabilizes HA and speeds up the dissociation of the fusion peptides (FPs). A buried salt-bridge between the N-terminus of HA stem domain and Asp112[SUB]2[/SUB] locks the FPs and may act as one of the pH sensors. In line with recent observations from simplified protein models, we find that, after the dissociation of FPs, a structural order-disorder transition in a loop connecting the central coiled-coil to the C-terminal domains produces a highly mobile HA. This motion suggests the existence of a long-lived asymmetric, or ``symmetry-broken'' intermediate during the HA conformational change. This intermediate conformation is consistent with models of hemifusion, and its early formation during the conformational change has implications for the aggregation seen in HA activity.
PMID: 27541202 DOI: 10.1021/acs.jpcb.6b06775
[PubMed - as supplied by publisher]
[h=1]Lowered pH Leads to Fusion Peptide Release and a Highly-Dynamic Intermediate of Influenza Hemagglutinin.[/h] Lin X, Noel JK, Wang Q, Ma J, Onuchic JN.
[h=3]Abstract[/h] Hemagglutinin (HA), the membrane-bound fusion protein of the Influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the dynamic consequences of the pH trigger, explicit-solvent molecular dynamics simulations were employed to investigate the initial stages of the HA transition. Our results indicate that lowered pH destabilizes HA and speeds up the dissociation of the fusion peptides (FPs). A buried salt-bridge between the N-terminus of HA stem domain and Asp112[SUB]2[/SUB] locks the FPs and may act as one of the pH sensors. In line with recent observations from simplified protein models, we find that, after the dissociation of FPs, a structural order-disorder transition in a loop connecting the central coiled-coil to the C-terminal domains produces a highly mobile HA. This motion suggests the existence of a long-lived asymmetric, or ``symmetry-broken'' intermediate during the HA conformational change. This intermediate conformation is consistent with models of hemifusion, and its early formation during the conformational change has implications for the aggregation seen in HA activity.
PMID: 27541202 DOI: 10.1021/acs.jpcb.6b06775
[PubMed - as supplied by publisher]