Structures and Mechanisms of Viral Membrane Fusion Proteins: Multiple Variations on a Common Theme

White, Judith M.; Delos, Sue E.; Brecher, Michael; Schornberg, Kathryn L.

doi:10.1080/10409230802058320

Cited by 773 publications

(950 citation statements)

References 301 publications

(414 reference statements)

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“…Thus, they are active participants that shape the energy landscape. There are multiple classes of fusogenic proteins, and there is significant variation in the number of fusion proteins per particle, suggesting additional biological requirements, presence of accessory proteins, or lipid compositions (2). Here, we consider how the class I fusogenic proteins might orchestrate energetic landscape-shaping mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…T he basic mechanisms of viral membrane fusion have been studied extensively, but major gaps remain in our understanding of the relative roles of lipidic intermediates and viral fusogenic proteins in lowering the energy barrier for the overall process (1)(2)(3)(4). The most common mechanistic hypothesis concerning enveloped viral fusion is that fusogenic proteins primarily serve to bring the target cell and viral membranes into proximity.…”

mentioning

confidence: 99%

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

Donald¹,

Zhang

Fiorin

et al. 2011

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

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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.T he basic mechanisms of viral membrane fusion have been studied extensively, but major gaps remain in our understanding of the relative roles of lipidic intermediates and viral fusogenic proteins in lowering the energy barrier for the overall process (1-4). The most common mechanistic hypothesis concerning enveloped viral fusion is that fusogenic proteins primarily serve to bring the target cell and viral membranes into proximity. Fusion occurs in a multistep process, in which the virus first binds to a specific receptor; this event and/or other environmental cues then cause a conformational change in the protein, leading to a metastable state with an exposed hydrophobic fusion peptide (FP) that binds to the target membrane. Once engaged with the bilayer, a second energetically favorable conformational change in the fusogenic protein then exerts a force pulling the FP toward the viral membrane, in effect reeling the host and viral membranes together.The conformational changes involved in the water-soluble portions of viral fusogenic proteins have been largely elucidated, but the roles of the membrane-binding FP and the C-terminal transmembrane (C-term-TM) anchor are less clear. After the crystal structure of the prefusogenic form of influenza hemagglutinin (HA) was solved...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Donald¹,

Zhang

Fiorin

et al. 2011

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

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“…Fusion is catalyzed by the HIV fusion protein gp41, which has Ϸ170 ectodomain residues outside the virus including a Ϸ20-residue N-terminal fusion peptide (HFP) that binds to target cell membranes (1). Studies of HIV with a truncated or mutated HFP showed that the HFP is crucial in the fusion process (2,3).…”

mentioning

confidence: 99%

A strong correlation between fusogenicity and membrane insertion depth of the HIV fusion peptide

Wang

Sun

Weliky³

2009

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

100

146

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Fusion between the membrane of HIV and the membrane of a host cell is a crucial step in HIV infection and is catalyzed by the binding of the fusion peptide domain (HFP) of the HIV gp41 protein to the host cell membrane. The HFP by itself induces vesicle fusion and is a useful model system to understand the fusion peptide/host cell membrane interaction. This article reports an experimental correlation between the membrane locations of different HFP constructs and their fusogenicities. The constructs were the HFP monomer with Val-2 to Glu-2 mutation (HFPmn_mut), wild type HFP monomer (HFPmn), and wild type HFP trimer (HFPtr). All constructs have predominant ␤ sheet structure in membranes with physiologically relevant cholesterol content. HFPmn_mut does not fuse vesicles, HFPmn has moderate fusion rate, and HFPtr has the putative oligomerization state of HIV gp41 and a very rapid fusion rate. The HFP membrane locations were probed with solid-state NMR measurements of distances between labeled carbonyl ( 13 CO) nuclei in the HFP backbone and lipid nuclei in the surface or interior regions of the membrane bilayer. HFPmn_mut is located at the membrane surface, HFPmn is inserted into a single membrane leaflet, and HFPtr is the most deeply inserted construct with contact with the center of the membrane. These results show a clear positive correlation between the insertion depths and the fusion activities of the HFP constructs. Other disease-causing enveloped viruses contain fusion peptides and this correlation may be a general structure-function model for these peptides.L ike many viruses that cause human disease, HIV is enveloped by a membrane obtained during virus budding from a previously infected host cell and infection of a new cell requires fusion between the viral membrane and the cell membrane. Fusion is catalyzed by the HIV fusion protein gp41, which has Ϸ170 ectodomain residues outside the virus including a Ϸ20-residue N-terminal fusion peptide (HFP) that binds to target cell membranes (1). Studies of HIV with a truncated or mutated HFP showed that the HFP is crucial in the fusion process (2, 3). Functionally critical fusion peptides are also found in fusion proteins of other enveloped viruses such as influenza and Ebola (1). Chemically synthesized peptides with HFP sequences have been developed as fusion model systems and provide information about HFP perturbation of target membranes. Free HFPs induce vesicle fusion and there are strong correlations between the mutation/activity relationships of HFP-induced fusion and HIV/host cell fusion (3).There have been some number of HFP structural studies, but in our view, there have not yet been clear correlations between HFP structure and fusogenic function. For example, membraneassociated HFP can adopt either helical or ␤ strand conformation and there has been effort to determine a correlation between conformation and fusogenicity. However, this work has resulted in conflicting models such as: (i) the helical conformation is fusogenic and the ␤ strand conformation i...

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“…Indeed, there is a long tradition in reconstituting fusion events using both biological and artificial membranes; such assays have been instrumental in unraveling the mechanisms underlying membrane merger, particularly in the field of viral fusion proteins (4). Similarly, the presence of appropriate combinations of SNAREs suffices to mediate fusion of artificial membranes: Liposomes containing synaptobrevin-2 are capable of lipid mixing with a second population of liposomes that contain SNAP-25 and syntaxin-1A (5).…”

mentioning

confidence: 99%

Inside insight to membrane fusion

Bogaart¹,

Jahn²

2011

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

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Structures and Mechanisms of Viral Membrane Fusion Proteins: Multiple Variations on a Common Theme

Cited by 773 publications

References 301 publications

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

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

A strong correlation between fusogenicity and membrane insertion depth of the HIV fusion peptide

Inside insight to membrane fusion

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