Early steps of the conformational change of influenza virus hemagglutinin to a fusion active state

Huang, Qiang; Rachakonda, P. Sivaramakrishna; Ludwig, Kai; Korte, Thomas; Böttcher, Christoph; Herrmann, Andreas

doi:10.1016/s0005-2736(03)00158-5

Cited by 64 publications

(56 citation statements)

References 58 publications

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“…Many fusion proteins (or its homologues) are responsible for the fusion between viral and cellular membranes. The fusion proteins usually undergo a conformational change to become fusogenically active, triggered by the acidic endosome or an elevated temperature (28). The formation of coiled-coil bundles, via HR1-HR2 interaction, is often a key conformational change in the transition of the fusion protein from the fusion-inactive to the fusion-active state (29).…”

Section: Discussionmentioning

confidence: 99%

The P2 capsid protein of the nonenveloped rice dwarf phytoreovirus induces membrane fusion in insect host cells

Zhou

Wei

et al. 2007

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

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Insect transmission is an essential process of infection for numerous plant and animal viruses. How an insect-transmissible plant virus enters an insect cell to initiate the infection cycle is poorly understood, especially for nonenveloped plant and animal viruses. The capsid protein P2 of rice dwarf virus (RDV), which is nonenveloped, is necessary for insect transmission. Here, we present evidence that P2 shares structural features with membrane-fusogenic proteins encoded by enveloped animal viruses. When RDV P2 was ectopically expressed and displayed on the surface of insect Spodoptera frugiperda cells, it induced membrane fusion characterized by syncytium formation at low pH. Mutational analyses identified the N-terminal and a heptad repeat as being critical for the membrane fusion-inducing activity. These results are corroborated with results from RDV-infected cells of the insect vector leafhopper. We propose that the RDV P2-induced membrane fusion plays a critical role in viral entry into insect cells. Our report that a plant viral protein can induce membrane fusion has broad significance in studying the mechanisms of virus entry into insect cells and insect transmission of nonenveloped plant and animal viruses.

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Section: Discussionmentioning

confidence: 99%

The P2 capsid protein of the nonenveloped rice dwarf phytoreovirus induces membrane fusion in insect host cells

Zhou

Wei

et al. 2007

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

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“…Nevertheless, the fusion results with the HA2 constructs indicate that there must be functionally important low pH-dependent interactions between the final conformations of HA2 subunits and/or between these conformations and the membranes. It has been suggested that protonation of HA leads to a loosening of the structure of HA as a result of electrostatic repulsion (31,32).…”

Section: Discussionmentioning

confidence: 99%

The Final Conformation of the Complete Ectodomain of the HA2 Subunit of Influenza Hemagglutinin Can by Itself Drive Low pH-dependent Fusion

Kim

Epand

Leikina

et al. 2011

Journal of Biological Chemistry

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One of the best characterized fusion proteins, the influenza virus hemagglutinin (HA), mediates fusion between the viral envelope and the endosomal membrane during viral entry into the cell. In the initial conformation of HA, its fusogenic subunit, the transmembrane protein HA2, is locked in a metastable conformation by the receptor-binding HA1 subunit of HA. Acidification in the endosome triggers HA2 refolding toward the final lowest energy conformation. Is the fusion process driven by this final conformation or, as often suggested, by the energy released by protein restructuring? Here we explored structural properties as well as the fusogenic activity of the full sized trimeric HA2(1-185) (here called HA2*) that presents the final conformation of the HA2 ectodomain. We found HA2* to mediate fusion between lipid bilayers and between biological membranes in a low pH-dependent manner. Two mutations known to inhibit HA-mediated fusion strongly inhibited the fusogenic activity of HA2*. At surface densities similar to those of HA in the influenza virus particle, HA2* formed small fusion pores but did not expand them. Our results confirm that the HA1 subunit responsible for receptor binding as well as the transmembrane and cytosolic domains of HA2 is not required for fusion pore opening and substantiate the hypothesis that the final form of HA2 is more important for fusion than the conformational change that generates this form.Fusion mediated by the influenza virus hemagglutinin (HA) protein is often considered as a prototype of biological fusion reactions. This fusion process is utilized by the virus to deliver its RNA into the host cell by merging the viral envelope with the membrane of an acidified endosome of the host cell. Each monomer of homotrimeric HA consists of two disulfide-linked subunits: HA1, responsible for receptor binding, and HA2. In the native neutral pH conformation of the HA protein, the HA1 subunit confines the HA2 subunit in a metastable state that has been termed the "spring-loaded" state (1-3). However, evidence from calorimetric studies indicates that the compact folded structure of the influenza hemagglutinin protein is not a kinetically trapped metastable high energy form (4, 5). In the neutral pH structure of intact HA, the functionally important N-terminal amphiphilic region of HA2, referred to as the fusion peptide, is hidden within the HA molecule. The low pH-triggered restructuring of HA unlocks HA2 and allows refolding of the HA2 subunit toward its final, low energy conformation, which consists of a hairpin structure with the fusion peptide and the transmembrane domain at the same end of the rigid rod. Although it is commonly assumed that the energy released by this restructuring drives rearrangements of membrane bilayers (6 -8), one may suggest an alternative hypothesis, i.e. that the final conformation itself is fusogenic.In our earlier work, to test the fusogenic properties of the final conformation of the HA2 subunit in the absence of

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“…We account here for the detailed properties of the glycoprotein HA, composed of two linked subunits HA1 and HA2, the latter anchoring HA to the viral envelope. At neutral pH, HA is not active (in a non-fusogenic state), but as the pH decreases due to acidification (proton entry into the endosome), a partial dissociation of the HA1 subunit results in a spring-loaded conformational change of HA2 into an active (fusogenic) state [13]. Consequently, the residence time of the Influenza virus genome within an endosome before fusion depends on the kinetics of endosome acidification.…”

Section: Is Composed By Eight Viral Ribonucleoproteins (Vrnps) (B)mentioning

confidence: 99%

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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Early steps of the conformational change of influenza virus hemagglutinin to a fusion active state

Cited by 64 publications

References 58 publications

The P2 capsid protein of the nonenveloped rice dwarf phytoreovirus induces membrane fusion in insect host cells

The P2 capsid protein of the nonenveloped rice dwarf phytoreovirus induces membrane fusion in insect host cells

The Final Conformation of the Complete Ectodomain of the HA2 Subunit of Influenza Hemagglutinin Can by Itself Drive Low pH-dependent Fusion

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

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