Leash in the groove mechanism of membrane fusion

Park, Heather E; Gruenke, Jennifer A.; White, Judith M.

doi:10.1038/nsb1012

Cited by 72 publications

(89 citation statements)

References 24 publications

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“…Moreover, a contribution to HR1-HR2 interaction comes from the extended region of HR2, which buries a large surface on the grooves of the HR1 trimer. Similar extended C peptide regions are present in inf luenza virus HA2 and paramyxovirus F and have been shown to have important roles in the membrane fusion process mediated by these two proteins (36,37). In the SARS-CoV S2 core structure, residues toward the N terminus of HR1 display increasing thermal parameters, reaching values Ͼ60 Å 2 .…”

Section: Discussionmentioning

confidence: 93%

Structure of a proteolytically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein

Supekar¹,

Bruckmann²,

Ingallinella³

et al. 2004

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

116

111

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A coronavirus (CoV) has recently been identified as the causative agent of the severe acute respiratory syndrome (SARS) in humans. CoVs enter target cells through fusion of viral and cellular membranes mediated by the viral envelope glycoprotein S. We have determined by x-ray crystallography the structure of a proteolytically stable core fragment from the heptad repeat (HR) regions HR1 and HR2 of the SARS-CoV S protein. We have also determined the structure of an HR1-HR2 S core fragment, containing a shorter HR1 peptide and a C-terminally longer HR2 peptide that extends up to the transmembrane region. In these structures, three HR1 helices form a parallel coiled-coil trimer, whereas three HR2 peptides pack in an oblique and antiparallel fashion into the coiled-coil hydrophobic grooves, adopting mixed extended and ␣-helical conformations as in postfusion paramyxoviruses F proteins structures. coiled-coil ͉ membrane fusion ͉ viral entry ͉ heptad repeat

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Section: Discussionmentioning

confidence: 93%

Structure of a proteolytically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein

Supekar¹,

Bruckmann²,

Ingallinella³

et al. 2004

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

116

111

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“…Although experiments have probed the fusion mechanism through mutation (8) and provided measures of fusion kinetics (9), there is a lack of structural information about how HA 2 transitions from the prefusion to postfusion conformations. Theoretical models have been suggested to describe the fusion mechanism based on the available experimental kinetic data (10)(11)(12).…”

mentioning

confidence: 99%

Order and disorder control the functional rearrangement of influenza hemagglutinin

Lin

Eddy

Noel

et al. 2014

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

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Influenza hemagglutinin (HA), a homotrimeric glycoprotein crucial for membrane fusion, undergoes a large-scale structural rearrangement during viral invasion. X-ray crystallography has shown that the pre-and postfusion configurations of HA 2 , the membranefusion subunit of HA, have disparate secondary, tertiary, and quaternary structures, where some regions are displaced by more than 100 Å. To explore structural dynamics during the conformational transition, we studied simulations of a minimally frustrated model based on energy landscape theory. The model combines structural information from both the pre-and postfusion crystallographic configurations of HA 2 . Rather than a downhill drive toward formation of the central coiled-coil, we discovered an order-disorder transition early in the conformational change as the mechanism for the release of the fusion peptides from their burial sites in the prefusion crystal structure. This disorder quickly leads to a metastable intermediate with a broken threefold symmetry. Finally, kinetic competition between the formation of the extended coiled-coil and C-terminal melting results in two routes from this intermediate to the postfusion structure. Our study reiterates the roles that cracking and disorder can play in functional molecular motions, in contrast to the downhill mechanical interpretations of the "springloaded" model proposed for the HA 2 conformational transition.protein folding | structure-based model H emagglutinin (HA) is a viral receptor-binding and membrane-fusion glycoprotein involved in the invasion of influenza virions into host cells (1). Structural rearrangements of HA during membrane fusion are crucial for the delivery of the viral genome. The postfusion conformation of HA shows considerable similarity to other viral fusion proteins and eukaryotic membrane receptors involved in intracellular vesicle trafficking (2), suggesting there may be common mechanisms in the function of these proteins. Therefore, HA may serve as a model system, allowing characterization of the molecular and energetic details that underlie its conformational transition to provide insights into general principles of membrane fusion (3).HA is a homotrimer consisting of two domains connected by disulfide bonds (4): a globular receptor binding domain (HA 1 ), and a coiled-coil membrane-fusion domain anchored to the viral membrane (HA 2 ). Recognized by the sialic acid receptor of a host cell, the intact virus enters the cell via endocytosis. Low pH in a late endosome then induces the dissociation of HA 1 from HA 2 (1) and an irreversible conformational transition of HA 2 . Experimentally, this conformational change can be triggered by either low pH, high temperature, or urea denaturation (5).Structures of HA in pre-and postfusion pH conformations have been solved by X-ray crystallography. The structure of the prefusion ectodomain contains both HA 1 and HA 2 , and was purified from influenza virions (4). A postfusion conformation of HA 1 and HA 2 were obtained from prefusion viral HA th...

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“…The crystal structure of the analogous envelope protein of influenza virus also shows only a short C-terminal segment folded back, which forms an asymmetric hairpin. In the case of influenza virus, a more distal, nonhelical C-terminal segment interacts with a portion of the N-helix trimer (7,32). Because MLV, like influenza virus, may not use the canonical six-helix bundle, it was of interest to investigate the effect of exogenously added peptides as well as endogenously expressed N-helix.…”

mentioning

confidence: 99%

Inhibition of Murine Leukemia Virus Envelope Protein (Env) Processing by Intracellular Expression of the Env N-Terminal Heptad Repeat Region

Silver

2005

J Virol

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A conserved structural motif in the envelope proteins of several viruses consists of an N-terminal, alphahelical, trimerization domain and a C-terminal region that refolds during fusion to bind the N-helix trimer. Interaction between the N and C regions is believed to pull viral and target membranes together in a crucial step during membrane fusion. For several viruses with type I fusion proteins, C regions pack as alpha-helices in the grooves between N-helix monomers, and exogenously added N-and C-region peptides block fusion by inhibiting the formation of the six-helix bundle. For other viruses, including influenza virus and murine leukemia virus (MLV), there is no evidence for comparably extended C-region alpha-helices, although a short, non-alpha-helical interaction structure has been reported for influenza virus. We tested candidate N-helix and C-region peptides from MLV for their ability to inhibit cell fusion but found no inhibitory activity. In contrast, intracellular expression of the MLV N-helix inhibited fusion by efficiently blocking proteolytic processing and intracellular transport of the envelope protein. The results highlight another mechanism by which the N-helix peptides can inhibit fusion.The envelope proteins of retroviruses, orthomyxoviruses, paramyxoviruses, and filoviruses have numerous structural similarities that suggest a common mechanism of membrane

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Leash in the groove mechanism of membrane fusion

Cited by 72 publications

References 24 publications

Structure of a proteolytically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein

Structure of a proteolytically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein

Order and disorder control the functional rearrangement of influenza hemagglutinin

Inhibition of Murine Leukemia Virus Envelope Protein (Env) Processing by Intracellular Expression of the Env N-Terminal Heptad Repeat Region

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