Dataset Information

Capturing Spontaneous Membrane Insertion of the Influenza Virus Hemagglutinin Fusion Peptide.

ABSTRACT: Hemagglutinin (HA) is a protein located on the surface of the influenza virus that mediates viral fusion to the host cellular membrane. During the fusion process the HA fusion peptide (HAfp), formed by the first 23 N-terminal residues of HA and structurally characterized by two alpha helices (Helix A and Helix B) tightly packed in a hairpin-like arrangement, is the only part of the virus in direct contact with the host membrane. After encountering the host cell, HAfp is believed to insert into the membrane, thereby initiating the fusion of the viral and host membranes. Detailed characterization of the interactions between the HAfp and cellular membrane is therefore of high relevance to the mechanism of viral entry into the host cell. Employing HMMM membrane representation with enhanced lipid mobility, we have performed a large set of independent simulations of unbiased membrane binding of HAfp. We have been able to capture spontaneous binding and insertion of HAfp consistently in nearly all the simulations. A reproducible membrane-bound configuration emerges from these simulations, despite employing a diverse set of initial configurations. Extension of several of the simulations into full membrane systems confirms the stability of the membrane-bound form obtained from HMMM binding simulations. The resulting model allows for the characterization of important interactions between the peptide and the membrane and the details of the binding process of the peptide for the first time. Upon membrane binding, Helix A inserts much deeper into the membrane than Helix B, suggesting that the former is responsible for hydrophobic anchoring of the peptide into the membrane. Helix B, in contrast, is found to establish major amphipathic interactions at the interfacial region thereby contributing to binding strength of HAfp.

SUBMITTER: Baylon JL

PROVIDER: S-EPMC5040216 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Capturing Spontaneous Membrane Insertion of the Influenza Virus Hemagglutinin Fusion Peptide.

Baylon Javier L JL Tajkhorshid Emad E

The journal of physical chemistry. B 20150608 25

Hemagglutinin (HA) is a protein located on the surface of the influenza virus that mediates viral fusion to the host cellular membrane. During the fusion process the HA fusion peptide (HAfp), formed by the first 23 N-terminal residues of HA and structurally characterized by two alpha helices (Helix A and Helix B) tightly packed in a hairpin-like arrangement, is the only part of the virus in direct contact with the host membrane. After encountering the host cell, HAfp is believed to insert into t ...[more]

PMID: 25996559

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Project description:The highly conserved cytoplasmic tail of influenza virus glycoprotein hemagglutinin (HA) contains three cysteines, posttranslationally modified by covalently bound fatty acids. While viral HA acylation is crucial in virus replication, its physico-chemical role is unknown. We used virus-like particles (VLP) to study the effect of acylation on morphology, protein incorporation, lipid composition, and membrane fusion. Deacylation interrupted HA-M1 interactions since deacylated mutant HA failed to incorporate an M1 layer within spheroidal VLP, and filamentous particles incorporated increased numbers of neuraminidase (NA). While HA acylation did not influence VLP shape, lipid composition, or HA lateral spacing, acylation significantly affected envelope curvature. Compared to wild-type HA, deacylated HA is correlated with released particles with flat envelope curvature in the absence of the matrix (M1) protein layer. The spontaneous curvature of palmitate was calculated by molecular dynamic simulations and was found to be comparable to the curvature values derived from VLP size distributions. Cell-cell fusion assays show a strain-independent failure of fusion pore enlargement among H2 (A/Japan/305/57), H3 (A/Aichi/2/68), and H3 (A/Udorn/72) viruses. In contradistinction, acylation made no difference in the low-pH-dependent fusion of isolated VLPs to liposomes: fusion pores formed and expanded, as demonstrated by the presence of complete fusion products observed using cryo-electron tomography (cryo-ET). We propose that the primary mechanism of action of acylation is to control membrane curvature and to modify HA's interaction with M1 protein, while the stunting of fusion by deacylated HA acting in isolation may be balanced by other viral proteins which help lower the energetic barrier to pore expansion.IMPORTANCE Influenza A virus is an airborne pathogen causing seasonal epidemics and occasional pandemics. Hemagglutinin (HA), a glycoprotein abundant on the virion surface, is important in both influenza A virus assembly and entry. HA is modified by acylation whose removal abrogates viral replication. Here, we used cryo-electron tomography to obtain three-dimensional images to elucidate a role for HA acylation in VLP assembly. Our data indicate that HA acylation contributes to the capability of HA to bend membranes and to HA's interaction with the M1 scaffold protein during virus assembly. Furthermore, our data on VLP and, by hypothesis, virus suggests that HA acylation, while not critical to fusion pore formation, contributes to pore expansion in a target-dependent fashion.

Dataset Information

Capturing Spontaneous Membrane Insertion of the Influenza Virus Hemagglutinin Fusion Peptide.

Publications

Capturing Spontaneous Membrane Insertion of the Influenza Virus Hemagglutinin Fusion Peptide.

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