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Transmembrane orientation and possible role of the fusogenic peptide from parainfluenza virus 5 (PIV5) in promoting fusion

Jason E. Donald, Yao Zhang, Giacomo Fiorin, Vincenzo Carnevale, David R. Slochower, Feng Gai, Michael L. Klein and William F. DeGrado
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 10 (March 8, 2011), pp. 3958-3963
Stable URL: http://www.jstor.org/stable/41061043
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Transmembrane orientation and possible role of the fusogenic peptide from parainfluenza virus 5 (PIV5) in promoting fusion
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Abstract

Membrane fusion is required for diverse biological functions ranging from viral infection to neurotransmitter release. Fusogenic proteins increase the intrinsically slow rate of fusion by coupling energetically downhill conformational changes of the protein to kinetically unfavorable fusion of the membrane-phospholipid bilayers. Class I viral fusogenic proteins have an N-terminal hydrophobic fusion peptide (FP) domain, important for interaction with the target membrane, plus a C-terminal transmembrane (C-term-TM) helical membrane anchor. The role of the water-soluble regions of fusogenic proteins has been extensively studied, but the contributions of the membrane-interacting FP and C-term-TM peptides are less well characterized. Typically, FPs are thought to bind to membranes at an angle that allows helix penetration but not traversal of the lipid bilayer. Here, we show that the FP from the paramyxovirus parainfluenza virus 5 fusogenic protein, F, forms an N-terminal TM helix, which self-associates into a hexameric bundle. This FP also interacts strongly with the C-term-TM helix. Thus, the fusogenic F protein resembles SNARE proteins involved in vesicle fusion by having water-soluble coiled coils that zipper during fusion and TM helices in both membranes. By analogy to mechanosensitive channels, the force associated with zippering of the water-soluble coiled-coil domain is expected to lead to tilting of the FP helices, promoting interaction with the C-term-TM helices. The energetically unfavorable dehydration of lipid headgroups of opposing bilayers is compensated by thermodynamically favorable interactions between the FP and C-term-TM helices as the coiled coils zipper into the membrane phase, leading to a pore lined by both lipid and protein.

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