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How proteins produce cellular membrane curvature

Key Points

  • This review discusses the physical mechanisms by which lipids and proteins generate the curvature of biological membranes. It surveys the main proteins of intracellular trafficking pathways that are known to participate in membrane bending and classifies them according to their probable mechanism of action.

  • We introduce membrane curvature and basic geometrical shapes, and show that all of the basic membrane shapes are involved in the generation of intracellular carriers. We distill the applicable theories of membrane deformation, elasticity and bending energy and introduce the effective shape and spontaneous curvature of lipids, which are factors that have an essential role in the generation of membrane curvature.

  • Based on the physics of membrane bending, we quantitatively analyse the conditions under which membrane lipids could create the curvatures that characterize intracellular carriers, and conclude that the requirements for membrane lipid composition are stringent and unusual and that lipid-based mechanisms for the generation of curvature require that proteins provide the necessary energy.

  • Reviewing the mechanism of tubular membrane formation by molecular motors that pull on flat membranes, we quantitatively confirm that it would take just a few molecular motors to induce the required curvature.

  • We formulate the main mechanisms by which membrane-associated proteins can induce curvature: the scaffold mechanism and the local spontaneous curvature mechanism. We formulate the criteria that proteins or their complexes have to satisfy in order to bend membranes according to these mechanisms.

  • Sufficiently rigid scaffold proteins can bend membranes using a membrane-adherent surface that causes the membrane to follow the contour of the protein. Proteins that insert into the lipid bilayer can bend membranes by changing the spontaneous curvature of the local monolayer. In all cases, the most probable way to generate membrane curvature is to use a combination of the scaffold and local spontaneous curvature mechanisms.

Abstract

Biological membranes exhibit various function-related shapes, and the mechanism by which these shapes are created is largely unclear. Here, we classify possible curvature-generating mechanisms that are provided by lipids that constitute the membrane bilayer and by proteins that interact with, or are embedded in, the membrane. We describe membrane elastic properties in order to formulate the structural and energetic requirements of proteins and lipids that would enable them to work together to generate the membrane shapes seen during intracellular trafficking.

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Figure 1: The beautiful and complex shapes of cells and cell organelles.
Figure 2: Determining membrane curvature.
Figure 3: Mechanisms by which proteins can generate membrane curvature.

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Acknowledgements

The work of J.Z. is supported by the Intramural Program of the National Institute of Child Health and Human Development, National Institutes of Health. The work of M.M.K. is supported by the Israel Science Foundation (ISF), The Binational US–Israel Science Foundation (BSF), and The EC Marie Curie Network 'Flippases'.

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DATABASES

Swiss-Prot

Arf GTPase-activating protein-1

Phospholipase A2

Sar1

Sec13

Sec23

Sec24

Interpro

BAR domain

ENTH domain

FURTHER INFORMATION

Heuser Lab

Joshua Zimmerberg's laboratory

Michael Kozlov's laboratory

Glossary

Coatomer proteins

Coat proteins that cover the cytoplasmic surfaces of coated vesicles that are involved in intracellular membrane trafficking at the endoplasmic reticulum and Golgi apparatus.

Dynamin

A large, 100-kDa GTPase that has been shown to form helical oligomers on membrane surfaces and to tubulate membranes. Dynamin is thought to mediate the pinching off of clathrin-coated and other vesicles during endocytosis.

Isotropic

The same in all directions.

Lysophospholipids

Phospholipids (or derivatives of phosphatidic acid) that lack one of their fatty acyl chains.

Amphipathic moieties

Portions of molecules or molecular complexes that have both hydrophobic and hydrophilic properties. For example, an amphipathic α-helix has a sequence of amino-acid residues that produces distinct hydrophilic and hydrophobic faces.

Clathrin–adaptor-protein complexes

Adaptor proteins recruit clathrin to membranes and concentrate specific transmembrane proteins in clathrin-coated areas of the membrane. Clathrin is a protein that exists in a trimeric form called a triskelion, and clathrin triskelia polymerize to form cage-like structures.

BAR domain

(Bin, amphiphysin, Rvs domain). A domain that is found in a large family of proteins. It forms a banana-like dimer, and binds to and tubulates lipid membranes.

Endophilins

A family of proteins that contain a BAR (Bin, amphiphysin, Rvs) domain with extra amphipathic helices. Endophilin-1 binds to and tubulates lipid membranes.

Spheroid

A geometric shape that is similar to a sphere but that is not exactly spherical (for example, a mis-shaped ball).

Epsin

A protein that contains an ENTH (epsin N-terminal homology) domain and is involved in clathrin-mediated endocytosis.

ENTH domain

(epsin N-terminal homology domain). A domain of epsin and several other proteins that binds to and tubulates lipid membranes.

Amphiphysin

A BAR (Bin, amphiphysin, Rvs)-domain-containing protein that binds to clathrin-coated vesicles during budding. Amphiphysin binds to and tubulates lipid membranes.

ArfGAP1

(Arf GTPase-activating protein-1). A small GTPase-activating protein that is responsible for catalysing Arf1 GTP hydrolysis. ArfGAP1 is needed to build up the coatomer protein (COP)I coats of intracellular transport vesicles.

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Zimmerberg, J., Kozlov, M. How proteins produce cellular membrane curvature. Nat Rev Mol Cell Biol 7, 9–19 (2006). https://doi.org/10.1038/nrm1784

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