Mechanisms of membrane fusion: disparate players and common principles

Key Points

  • Membrane fusion in vivo involves the coordinated and leak-free merger of two bilayers. It requires that membranes are brought into close proximity, that there is local bilayer destabilization and that the overall process is given directionality. Fusion proteins control this process in cellular fusion events and these diverse proteins should therefore share these common activities.

  • Energy is required for loosely tethered membranes to fuse: protein-free membranes must be brought into very close proximity, and initially a hemifusion intermediate is thought to form that proceeds through fusion-pore opening and dilation stages to full merging of the membranes.

  • Fusion proteins (or complexes of fusion proteins) function by lowering energy barriers and giving directionality. Fusion proteins can be structurally very different and yet achieve the same end point. Tethering of membranes has been well studied, but how to make membranes fusogenic has been less well characterized.

  • The induction of membrane-curvature stress in membranes by fusion proteins might turn out to be a common underappreciated feature of many fusion proteins that makes membranes fusogenic. In many cases membrane curvature stress can be achieved by shallow insertions into one monolayer of the membrane.

  • Curvature induction might be mediated by the fusion peptides or loops of the viral fusion proteins, by C2 domains during Ca2+-dependent exocytosis, by Ig-like domains in cell–cell fusion events, by membrane insertion of hydrophobic regions of tethering factors, or by oligomerization by dynamin superfamily GTPases (for example, during mitochondrial fusion).

  • Future studies will have to address how close membrane proximity and curvature induction are coordinated in space and time in response to specific cellular cues.

Abstract

Membrane fusion can occur between cells, between different intracellular compartments, between intracellular compartments and the plasma membrane and between lipid-bound structures such as viral particles and cellular membranes. In order for membranes to fuse they must first be brought together. The more highly curved a membrane is, the more fusogenic it becomes. We discuss how proteins, including SNAREs, synaptotagmins and viral fusion proteins, might mediate close membrane apposition and induction of membrane curvature to drive diverse fusion processes. We also highlight common principles that can be derived from the analysis of the role of these proteins.

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Figure 1: The broad spectrum of membrane-fusion events.
Figure 2: The hemifusion model for bilayer fusion.
Figure 3: Molecular 'sieving'.
Figure 4: Hairpin-like structures in membrane fusion.
Figure 5: Membrane insertions and bending by membrane-fusion molecules.
Figure 6: Ca2+-dependent membrane interaction of C2 domains.
Figure 7: Multiple-C2-domain-containing proteins.

Accession codes

Accessions

GenBank/EMBL/DDBJ

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Acknowledgements

We thank the members of the McMahon laboratory and F. Cohen for discussing the material. We thank M. Kozlov for advice on illustrating the lipid rearrangements. S. M. was supported by an EMBO fellowship (ALTF212006) and the McMahon laboratory is supported by the Medical Research Council (UK).

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DATABASES

Protein Data Bank 

1BYN

1DQV

1HTM

1IBN

1JOC

1MCP

1SFC

1UOW

2CMZ

2HMG

FirstGlance in Jmol (3D structures) 

1BYN

1DQV

1HTM

1IBN

1JOC

1MCP

1SFC

1UOW

2CMZ

2HMG

FURTHER INFORMATION

Harvey T. McMahon's homepage

Leiden muscular dystrophy pages: dysferlin

SNPs3D of ferlins

Structural Classification of Proteins (SCOP): Synaptotagmin-like

Synaptotagmin home page

Glossary

Syncytium

A cell that contains multiple nuclei and that is formed either by cell–cell fusion or by incomplete cell division.

Hemifusion

An intermediate stage during membrane fusion that is characterized by the merger of only the contacting monolayers and not the two distal monolayers.

SNARE

(soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor). SNARE proteins are a family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity in vesicle trafficking. They can be divided into vesicle-associated (v)-SNAREs and target-membrane-associated (t)-SNAREs on the basis of their localization.

Fusion peptide or loop

A short hydrophobic or amphiphilic peptide in a viral fusion protein that is normally only exposed during fusion and is proposed to insert into the cellular membrane.

Liposome

An artificial, bilayer-bound structure that is composed of lipids and resembles an intracellular transport vesicle.

Dynamin superfamily

A family of GTP-binding proteins that mediate oligomerization-dependent membrane remodelling events.

Fusogen

An agent that has the ability to promote fusion between two membranes.

Syncytin

A mammalian protein that is derived from a retrovirus. Syncytins function in cell–cell fusion during trophoblast formation.

Immunoglobulin (Ig)-like domain

A common domain that is found in extracellular proteins and is composed largely of β-sheets. Ig domains are the structural unit of antibodies.

C2 domain

A domain found in many intracellular proteins that mediate Ca2+-dependent protein–protein and protein–membrane interactions.

AAA-ATPases

(ATPases associated with diverse cellular activities). Enzymes that translate the chemical energy that is stored in ATP into a mechanical force.

NSF

(N-ethylmaleimide-sensitive fusion protein). An AAA-ATPase that uses ATP hydrolysis to disassemble the SNARE complex.

Aliphatic chain

A backbone of carbon atoms that lack aromatic groups. In cellular membranes, the aliphatic hydrocarbon chains of phospholipids and sphingolipids form the hydrophobic core of the membrane.

Rab GTPase

A small GTP-binding protein that regulates membrane traffic by interacting with effector proteins.

Endosomes

Various intracellular compartments that are the central sorting stations for molecules that are either derived mainly from the plasma membrane or taken up from the extracellular medium.

FYVE domain

A protein domain that is named after the first four proteins in which it was found (Fab1, YOTB/ZK632.12, Vac1 and EEA1) and that binds to the membrane lipid phosphatidylinositol-3-phosphate.

Dense-core granules

Vesicles that are 200–300 nm in diameter and are seen as electron dense by electron microscopy. In some cells they undergo Ca2+-dependent exocytosis.

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Martens, S., McMahon, H. Mechanisms of membrane fusion: disparate players and common principles. Nat Rev Mol Cell Biol 9, 543–556 (2008). https://doi.org/10.1038/nrm2417

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