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Mechanics of membrane fusion.

Chernomordik LV, Kozlov MM - Nat. Struct. Mol. Biol. (2008)

Bottom Line: Diverse membrane fusion reactions in biology involve close contact between two lipid bilayers, followed by the local distortion of the individual bilayers and reformation into a single, merged membrane.We consider the structures and energies of the fusion intermediates identified in experimental and theoretical work on protein-free lipid bilayers.On the basis of this analysis, we then discuss the conserved fusion-through-hemifusion pathway of merger between biological membranes and propose that the entire progression, from the close juxtaposition of membrane bilayers to the expansion of a fusion pore, is controlled by protein-generated membrane stresses.

View Article: PubMed Central - PubMed

Affiliation: Section on Membrane Biology, Laboratory of Cellular and Molecular Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1855, USA. chernoml@mail.nih.gov

ABSTRACT
Diverse membrane fusion reactions in biology involve close contact between two lipid bilayers, followed by the local distortion of the individual bilayers and reformation into a single, merged membrane. We consider the structures and energies of the fusion intermediates identified in experimental and theoretical work on protein-free lipid bilayers. On the basis of this analysis, we then discuss the conserved fusion-through-hemifusion pathway of merger between biological membranes and propose that the entire progression, from the close juxtaposition of membrane bilayers to the expansion of a fusion pore, is controlled by protein-generated membrane stresses.

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Hypothetical pathway of biological fusion powered by protein-generated membrane stresses. (a) In the initial state, apposing membrane bilayers are separated by at least a 10–20 nm gap. The contact might involve protein fusogens themselves or be mediated by specialized tethering molecules (green shapes). (b) Fusion proteins induce local bending of membrane bilayer(s) and establish very close contact between the membranes. Generation of large membrane curvature might involve shallow insertion of amphiphilic protein domains (red shapes) into the membrane10,62. The highly stressed and protein-depleted tops of the bilayer bulges are primed for hemifusion and pore opening10,29,56,57. (c) Activated fusion proteins (blue shapes) might drive fusion pore expansion by assembling into an interconnected protein coat surrounding the fusion site119. This membrane-associated fusion coat has an intrinsic curvature opposite to that of the budding and fission coats. The coat, bending toward its preferred curvature, deforms the underlying membrane and produces tension that drives fusion and expands the fusion pore.
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Figure 3: Hypothetical pathway of biological fusion powered by protein-generated membrane stresses. (a) In the initial state, apposing membrane bilayers are separated by at least a 10–20 nm gap. The contact might involve protein fusogens themselves or be mediated by specialized tethering molecules (green shapes). (b) Fusion proteins induce local bending of membrane bilayer(s) and establish very close contact between the membranes. Generation of large membrane curvature might involve shallow insertion of amphiphilic protein domains (red shapes) into the membrane10,62. The highly stressed and protein-depleted tops of the bilayer bulges are primed for hemifusion and pore opening10,29,56,57. (c) Activated fusion proteins (blue shapes) might drive fusion pore expansion by assembling into an interconnected protein coat surrounding the fusion site119. This membrane-associated fusion coat has an intrinsic curvature opposite to that of the budding and fission coats. The coat, bending toward its preferred curvature, deforms the underlying membrane and produces tension that drives fusion and expands the fusion pore.

Mentions: Accumulating evidence suggests that the main role of the fusion proteins is to generate and control the membrane elastic stresses that, in analogy to lipid bilayer fusion, seem to be key in biological fusion. It has been proposed that the critical step in the initiation of lipid rearrangements by the fusion proteins consists in local bending of membrane bilayers into ‘dimples’56 (also referred to as a ‘nipples’29) pointing toward the adjacent membrane (Fig. 3). Such membrane bending brings the membrane bilayers into close contact56,57 and primes the protein-depleted, stressed tops of the bilayer bulges for fusion by lowering the energy barriers for hemifusion and pore opening29,56,57. How do the proteins do this job? Several models suggest that fusion is driven by the energy released in the course of formation of the hairpin conformation and transmitted to the membranes through TMDs and fusion peptides anchoring the fusogens to the membrane matrix. However, although this refolding of fusion protein ectodomains is most likely important in fusion, the diverse fusion peptides of different proteins are clearly not just membrane anchors. Mutations in the fusion peptide of influenza hemagglutinin, including those that do not change hydrophobicity but do disturb the fusion peptide’s boomerang-like structure, have pronounced effects on the fusogenic activity of hemagglutinin109,110. The importance of peptide–membrane interactions in fusion is also emphasized by the ability of fusion-associated small transmembrane (FAST) proteins of non-enveloped viruses, which do not form rigid hairpin structures, to fuse infected and uninfected cells111. Finally, it seems that fusion loops of the fusogen of vesicular stomatitis virus112 are too short to serve as ‘anchors’ to transfer significant energy to the membrane, suggesting that their most important function may be disrupting the structure of the bilayers rather than anchoring the ectodomain of the protein to the target membrane.


Mechanics of membrane fusion.

Chernomordik LV, Kozlov MM - Nat. Struct. Mol. Biol. (2008)

Hypothetical pathway of biological fusion powered by protein-generated membrane stresses. (a) In the initial state, apposing membrane bilayers are separated by at least a 10–20 nm gap. The contact might involve protein fusogens themselves or be mediated by specialized tethering molecules (green shapes). (b) Fusion proteins induce local bending of membrane bilayer(s) and establish very close contact between the membranes. Generation of large membrane curvature might involve shallow insertion of amphiphilic protein domains (red shapes) into the membrane10,62. The highly stressed and protein-depleted tops of the bilayer bulges are primed for hemifusion and pore opening10,29,56,57. (c) Activated fusion proteins (blue shapes) might drive fusion pore expansion by assembling into an interconnected protein coat surrounding the fusion site119. This membrane-associated fusion coat has an intrinsic curvature opposite to that of the budding and fission coats. The coat, bending toward its preferred curvature, deforms the underlying membrane and produces tension that drives fusion and expands the fusion pore.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2548310&req=5

Figure 3: Hypothetical pathway of biological fusion powered by protein-generated membrane stresses. (a) In the initial state, apposing membrane bilayers are separated by at least a 10–20 nm gap. The contact might involve protein fusogens themselves or be mediated by specialized tethering molecules (green shapes). (b) Fusion proteins induce local bending of membrane bilayer(s) and establish very close contact between the membranes. Generation of large membrane curvature might involve shallow insertion of amphiphilic protein domains (red shapes) into the membrane10,62. The highly stressed and protein-depleted tops of the bilayer bulges are primed for hemifusion and pore opening10,29,56,57. (c) Activated fusion proteins (blue shapes) might drive fusion pore expansion by assembling into an interconnected protein coat surrounding the fusion site119. This membrane-associated fusion coat has an intrinsic curvature opposite to that of the budding and fission coats. The coat, bending toward its preferred curvature, deforms the underlying membrane and produces tension that drives fusion and expands the fusion pore.
Mentions: Accumulating evidence suggests that the main role of the fusion proteins is to generate and control the membrane elastic stresses that, in analogy to lipid bilayer fusion, seem to be key in biological fusion. It has been proposed that the critical step in the initiation of lipid rearrangements by the fusion proteins consists in local bending of membrane bilayers into ‘dimples’56 (also referred to as a ‘nipples’29) pointing toward the adjacent membrane (Fig. 3). Such membrane bending brings the membrane bilayers into close contact56,57 and primes the protein-depleted, stressed tops of the bilayer bulges for fusion by lowering the energy barriers for hemifusion and pore opening29,56,57. How do the proteins do this job? Several models suggest that fusion is driven by the energy released in the course of formation of the hairpin conformation and transmitted to the membranes through TMDs and fusion peptides anchoring the fusogens to the membrane matrix. However, although this refolding of fusion protein ectodomains is most likely important in fusion, the diverse fusion peptides of different proteins are clearly not just membrane anchors. Mutations in the fusion peptide of influenza hemagglutinin, including those that do not change hydrophobicity but do disturb the fusion peptide’s boomerang-like structure, have pronounced effects on the fusogenic activity of hemagglutinin109,110. The importance of peptide–membrane interactions in fusion is also emphasized by the ability of fusion-associated small transmembrane (FAST) proteins of non-enveloped viruses, which do not form rigid hairpin structures, to fuse infected and uninfected cells111. Finally, it seems that fusion loops of the fusogen of vesicular stomatitis virus112 are too short to serve as ‘anchors’ to transfer significant energy to the membrane, suggesting that their most important function may be disrupting the structure of the bilayers rather than anchoring the ectodomain of the protein to the target membrane.

Bottom Line: Diverse membrane fusion reactions in biology involve close contact between two lipid bilayers, followed by the local distortion of the individual bilayers and reformation into a single, merged membrane.We consider the structures and energies of the fusion intermediates identified in experimental and theoretical work on protein-free lipid bilayers.On the basis of this analysis, we then discuss the conserved fusion-through-hemifusion pathway of merger between biological membranes and propose that the entire progression, from the close juxtaposition of membrane bilayers to the expansion of a fusion pore, is controlled by protein-generated membrane stresses.

View Article: PubMed Central - PubMed

Affiliation: Section on Membrane Biology, Laboratory of Cellular and Molecular Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1855, USA. chernoml@mail.nih.gov

ABSTRACT
Diverse membrane fusion reactions in biology involve close contact between two lipid bilayers, followed by the local distortion of the individual bilayers and reformation into a single, merged membrane. We consider the structures and energies of the fusion intermediates identified in experimental and theoretical work on protein-free lipid bilayers. On the basis of this analysis, we then discuss the conserved fusion-through-hemifusion pathway of merger between biological membranes and propose that the entire progression, from the close juxtaposition of membrane bilayers to the expansion of a fusion pore, is controlled by protein-generated membrane stresses.

Show MeSH
Related in: MedlinePlus