Kinetics of the low pH-induced conformational changes and fusogenic activity of influenza hemagglutinin

Krumbiegel, M.; Herrmann, Andreas; Blumenthal, Robert

doi:10.1016/s0006-3495(94)80721-0

Cited by 57 publications

(77 citation statements)

References 19 publications

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“…Below pH Ϸ 4.5, the local concentration of proton-bound HA is maximized and the relatively slow conformational rearrangements (extension followed by collapse) determine the overall hemifusion rate. The pH at which activation is no longer limiting agrees well with the pH at which the measured rate of HA conformational change becomes very rapid, as measured by fluorescence changes in detergentsolubilized HA from the same, X31, influenza strain (35).…”

Section: Discussionsupporting

confidence: 69%

Single-particle kinetics of influenza virus membrane fusion

Floyd¹,

Ragains²,

Skehel³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

263

389

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Membrane fusion is an essential step during entry of enveloped viruses into cells. Conventional fusion assays are generally limited to observation of ensembles of multiple fusion events, confounding more detailed analysis of the sequence of the molecular steps involved. We have developed an in vitro, two-color fluorescence assay to monitor kinetics of single virus particles fusing with a target bilayer on an essentially fluid support. Analysis of lipid-and content-mixing trajectories on a particle-by-particle basis provides evidence for multiple, long-lived kinetic intermediates leading to hemifusion, followed by a single, rate-limiting step to pore formation. We interpret the series of intermediates preceding hemifusion as a result of the requirement that multiple copies of the trimeric hemagglutinin fusion protein be activated to initiate the fusion process.enveloped viruses ͉ lipid bilayer ͉ single molecule ͉ virus entry

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Section: Discussionsupporting

confidence: 69%

Single-particle kinetics of influenza virus membrane fusion

Floyd¹,

Ragains²,

Skehel³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

263

389

View full text Add to dashboard Cite

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“…We reported here a good agreement between the WKB approximation (Equation 23) with the Monte-Carlo simulations of the Markov jump process, with the transition rates r(X, c) and l(X) given by Equation (19), and the experimental values of [28] ( Figure 3B, model parameters are summarized in Table 2). The WKB solution is very close to the Markov jump simulations, especially for pH values ≥ 5.8, where the fusion takes place (Section 2.3 below).…”

Section: Rate Of Ha Conformational Changesupporting

confidence: 72%

“…To compute the mean time for HA conformation to change as the pH drops, we first extracted the forward and backward proton binding rates by converting the HA conformational change kinetics, obtained from experimental data at various pH [28] into rate constants.…”

Section: Markov Jump Model Of Ha Conformational Changementioning

confidence: 99%

“…When the number of bound protons reaches a given threshold, the HA trimer changes conformation into a fusogenic state. (B) MFPT of a discrete Markov jump process with transition rates r(X, c) and l(X) to a critical threshold n T = 6 is estimated with Monte-Carlo simulations (N = 1000) (solid red line), and compared with WKB approximation (solid black line) and experimental data points [28].…”

Section: Rate Of Ha Conformational Changementioning

confidence: 99%

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Stochastic Model of Acidification, Activation of Hemagglutinin and Escape of Influenza Viruses from an Endosome

et al. 2017

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Influenza viruses enter the cell inside an endosome. During the endosomal journey, acidification triggers a conformational change of the virus spike protein hemagglutinin (HA) that results in escape of the viral genome from the endosome into the cytoplasm. It is still unclear how the interplay between acidification and HA conformation changes affects the kinetics of the viral endosomal escape. We develop here a stochastic model to estimate the change of conformation of HAs inside the endosome nanodomain. Using a Markov process, we model the arrival of protons to HA binding sites and compute the kinetics of their accumulation. We compute the Mean First Passage Time (MFPT) of the number of HA bound sites to a threshold, which is used to estimate the HA activation rate for a given pH (i.e. proton concentration). The present analysis reveals that HA proton binding sites possess a high chemical barrier, ensuring a stability of the spike protein at sub-acidic pH. We predict that activating more than 3 adjacent HAs is necessary to trigger endosomal fusion and this configuration prevents premature release of viruses from early endosomes.

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“…21). Because the conformational change and exposure of hydrophobic sequences of HA is very rapid, particularly at optimal conditions of pH 5.0 at 37°C (4,39,40), viruses can interact with remaining lysolipid micelles via those hydrophobic sequences before or instead of binding to target membranes. Even if the interaction is reversible, it may be responsible for a conformational transition of HA to a fusion-inactivated state by interaction with lysolipids and/or be due to the delayed contact with the target membrane.…”

Section: Interaction Of Sl-lpc With Intact and Bromelain-treated Virumentioning

confidence: 99%

Lysolipids Do Not Inhibit Influenza Virus Fusion by Interaction with Hemagglutinin

Baljinnyam¹,

Schroth‐Diez²,

Korte

et al. 2002

Journal of Biological Chemistry

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The interaction of a spin-labeled lysophosphatidylcholine analog with intact and bromelain-treated influenza viruses as well as with the bromelain-solubilized hemagglutinin ectodomain has been studied. The inhibition of fusion of influenza viruses with erythrocytes by the lysophosphatidylcholine analog was similar to that observed for non-labeled lysophosphatidylcholine. Only a weak interaction of the lysophosphatidylcholine analog with the hemagglutinin ectodomain was observed even upon triggering the conformational change of the ectodomain at a low pH. A significant interaction of spin-labeled lysophosphatidylcholine with the hemagglutinin ectodomain of intact viruses was observed neither at neutral nor at low pH, whereas a strong interaction of the lipid analog with the viral lipid bilayer was evident. We suggest that the high number of lipid binding sites of the virus bilayer and their affinity compete efficiently with binding sites of the hemagglutinin ectodomain. We conclude that the inhibition of influenza virus fusion by lysolipids is not mediated by binding to the hemagglutinin ectodomain, preventing its interaction with the target membrane. The results unambiguously argue for an inhibition mechanism based on the action of lysolipid inserted into the lipid bilayer.

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Kinetics of the low pH-induced conformational changes and fusogenic activity of influenza hemagglutinin

Cited by 57 publications

References 19 publications

Single-particle kinetics of influenza virus membrane fusion

Single-particle kinetics of influenza virus membrane fusion

Stochastic Model of Acidification, Activation of Hemagglutinin and Escape of Influenza Viruses from an Endosome

Lysolipids Do Not Inhibit Influenza Virus Fusion by Interaction with Hemagglutinin

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