Membrane interaction and structure of the transmembrane domain of influenza hemagglutinin and its fusion peptide complex

Institute of Chemistry, Academia Sinica, Taipei, Taiwan 11529, Republic of China.
BMC Biology (Impact Factor: 7.98). 02/2008; 6(1):2. DOI: 10.1186/1741-7007-6-2
Source: PubMed


To study the organization and interaction with the fusion domain (or fusion peptide, FP) of the transmembrane domain (TMD) of influenza virus envelope glycoprotein for its role in membrane fusion which is also essential in the cellular trafficking of biomolecules and sperm-egg fusion.
The fluorescence and gel electrophoresis experiments revealed a tight self-assembly of TMD in the model membrane. A weak but non-random interaction between TMD and FP in the membrane was found. In the complex, the central TMD oligomer was packed by FP in an antiparallel fashion. FP insertion into the membrane was altered by binding to TMD. An infrared study exhibited an enhanced membrane perturbation by the complex formation. A model was built to illustrate the role of TMD in the late stages of influenza virus-mediated membrane fusion reaction.
The TMD oligomer anchors the fusion protein in the membrane with minimal destabilization to the membrane. Upon associating with FP, the complex exerts a synergistic effect on the membrane perturbation. This effect is likely to contribute to the complete membrane fusion during the late phase of fusion protein-induced fusion cascade. The results presented in the work characterize the nature of the interaction of TMD with the membrane and TMD in a complex with FP in the steps leading to pore initiation and dilation during virus-induced fusion. Our data and proposed fusion model highlight the key role of TMD-FP interaction and have implications on the fusion reaction mediated by other type I viral fusion proteins. Understanding the molecular mechanism of membrane fusion may assist in the design of anti-viral drugs.

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Available from: Yu-Tsan Liu, Jan 22, 2014
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    • "Following this idea, Chang et al. explored the existence of actual interactions between HA FP and TMD and its involvement in the IFV fusion process (Chang et al., 2008). They used fluorescently labeled peptides and model membranes, to assay formation of complexes between FP and TMD domains. "
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    • "Our analysis indicates that amino acids substitutions in the pre-anchor region of E1 (V333A, L337A and M347A) strongly reduced the amount of cross-recurrence suggesting a possible interaction between this region and the domain containing the fusion peptide. Interestingly, a similar association of the trans-membrane domain with the fusion peptide seems to represent a key event in the fusion process of influenza virus [37]. If the interaction between these two domains of E1 is required to complete the fusion process, this step could be a potential target for antiviral fusion inhibitors. "
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    • "). The active fusion core of viruses such as influenza and the human immunodeficiency virus constitutes a 6-helix bundle consisting of two helices from each fusion protein in the trimer (Skehel and Wiley, 2000; Melikyan et al., 2000; Russel et al., 2001; Chang et al., 2008). Its formation can be prevented by antiviral peptides that mimic the helices and compete with the protein-protein interactions that give rise to the fusion core (Hsieh and Hsu JT., 2007; Stevens and Donis, 2007). "
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