A Cost–Benefit Analysis of the Physical Mechanisms of Membrane Curvature

REVIEW A cost–benefit analysis of the physical mechanisms of membrane curvature Jeanne C. Stachowiak, Frances M. Brodsky and Elizabeth A. Miller Many cellular membrane-bound structures exhibit distinct curvature that is driven by the physical properties of their lipid and protein constituents. Here we review how cells manipulate and control this curvature in the context of dynamic events such as vesicle-mediated membrane traffic. Lipids and cargo proteins each contribute energy barriers that must be overcome during vesicle formation. In contrast, protein coats and their associated accessory proteins drive membrane bending using a variety of interdependent physical mechanisms. We survey the energy costs and drivers involved in membrane curvature, and draw a contrast between the stochastic contributions of molecular crowding and the deterministic assembly of protein coats. These basic principles also apply to other cellular examples of membrane bending events, including important disease-related problems such as viral egress. Cellular membranes, which partition eukaryotic cells into distinct The current challenge is to understand how the cooperative energy compartments, possess an intrinsic simplicity that belies their com- contributions of multiple active components drive bending of complex plex gymnastics during normal cellular function. The majority of membranes composed of diverse lipids and proteins. Cellular membrane cellular membranes are planar lipid bilayers. These are influenced by bending also occurs in the context of organized tissue or in the face of intrinsic and extrinsic forces to generate the curved structures that are turgor pressure, factors that introduce additional energy barriers, neces- associated with diverse cellular architectures (Fig. 1). Curved mem- sitating additional force. Here we review the multiple physical mecha- branes can be relatively stable structures — such as those surrounding nisms that influence membrane bending and perform an accounting nuclear pores — or can be transient, such as transport vesicles that are of their relative energy contributions to cellular membrane deforma- continually produced and consumed during membrane and protein tion. We focus primarily on vesicle trafficking pathways, although the traffic. In each case, these structures form from the action of proteins same fundamental principles can also help us understand curvature in that use distinct mechanisms to exert forces that sculpt the requisite other cellular contexts. We first consider the physical properties of lipids membrane architecture1–3. Considerable insight into the mechanisms and cargo, and the barriers they pose to membrane bending. We then of membrane curvature has been gained from minimally reconstituted discuss the drivers of membrane curvature and the different physical systems, largely based on shape changes exerted on synthetic liposomes mechanisms that they employ. Together these considerations define by individual protein components. These systems have established that, an integrated set of parameters that operate during intracellular and in many instances, physical properties associated with a single protein plasma membrane bending. The energy cost-benefit analysis that we are sufficient to induce curvature. In recent years, experimental sys- describe here becomes particularly important in considering membrane tems have focused on two principles: membrane insertion and pro- curvature under pathological conditions, for example where pathogens tein scaffolding. However, more recent theoretical and experimental induce uptake by cells, or when viruses bud from the plasma membrane, analyses have suggested that molecular crowding is also an important liberating themselves for additional rounds of infection. driver of curvature, in a manner that can either augment the action of protein scaffolds, or oppose it. Finally, scaffold rigidity has also The energy costs of bending a membrane been suggested to be a key factor contributing to membrane bending. Most cellular phospholipids have a cylindrical shape and therefore self- Examples of each of these types of curvature drivers can be found at assemble into planar bilayers. According to the simplified two-dimen- different sites within the cell (Fig. 1), where different bending require- sional description of membrane mechanics by Canham4 and Helfrich5, ments are likely to be specified by the lipid and protein composition of deforming bilayers into curved shapes encounters two energy barriers: the underlying membrane. resistance to membrane bending and resistance to membrane stretching. Jeanne C. Stachowiak is in the Department of Biomedical Engineering, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA. Frances M. Brodsky is in the Departments of Bioengineering and Therapeutic Sciences, Pharmaceutical Chemistry and Microbiology and Immunology, The G.W. Hooper Foundation, University of California, San Francisco, California 94143, USA. Elizabeth A. Miller is in the Department of Biological Sciences, Columbia University, New York, New York 10027, USA. e-mail: [email protected] NATURE CELL BIOLOGY VOLUME 15 | NUMBER 9 | SEPTEMBER 2013 1019 © 2013 Macmillan Publishers Limited. All rights reserved REVIEW Cilia Clathrin-coated vesicles Caveolae Viral budding Cargo oligomerization Septins Caveolin Secretory granules ESCRTs Retromer Cargo aggregation COPI vesicles Multivesicular bodies COPII vesicles ESCRTs Mitochondrial cristae ATP synthase Nuclear pores ER tubules Reticulons Nups Figure 1 Cellular sites of membrane curvature. The membranes of eukaryotic cells often display curvature; some are dynamic (for example, transport vesicles, endosomal tubules and viral buds) and others more static (for example, nuclear pores, cilia, endoplasmic reticulum (ER) tubules and mitochondrial cristae). Each of these examples of membrane curvature is created by physical effects that derive from both lipid and protein sources. Self-assembling proteins can scaffold membranes (clathrin, COPI, COPII, nucleoporins, caveolins, reticulons, retromer, ESCRTs and septins). Asymmetric lipid and protein insertion can drive curvature by the bilayer couple model and molecular crowding effects (secretory granule cargoes, reticulons, caveolins, viral matrix proteins and mitochondrial ATP synthase). COPI structure reproduced with permission from ref. 46, © 2004 AAAS. COPII structure reproduced from ref. 45, clathrin structure from ref. 83 and retromer model from ref. 84. Septin model reproduced with permission from ref. 85, © 2009 Elsevier. ESCRT structure reproduced with permission from ref. 86, © 2013 Wiley. As discussed below, bending rigidity generally poses the larger barrier to membrane surface. This process increases steric repulsion among cargo membrane curvature, except in cases where membrane tension is signifi- molecules that can be expected to oppose membrane curvature (Fig. 2a). cantly raised by turgor pressure6, osmotic shock, or action of the cytoskel- Such effects are amplified when cargo proteins display asymmetry across eton7. Many biological membranes, such as the plasma membranes of the bilayer such that lumenal domains are significantly larger than their red blood cells8, are thought to have significant spontaneous curvature, a corresponding cytoplasmic domains. An extreme example of this topol- preferred curvature5 that typically arises from a difference in lipid compo- ogy is the family of lipid-anchored proteins, glycosylphosphorylinosi- sition between the two leaflets of the membrane9. Spontaneous curvature is tol (GPI)-anchored proteins. These abundant and diverse cell surface likely to have a significant influence on the curvature of cellular structures, proteins expose their entire molecular mass on the lumenal surface of though this contribution remains difficult to quantify, as it arises from transport vesicles11. Concentration of these proteins at budding sites may highly localized, often transient, differences in membrane composition. create significant lateral pressure within the membrane that could induce local negative (away from the membrane) curvature (Fig. 2b). Cargo proteins The idea that unbalanced steric pressure among membrane-bound An under-appreciated player in the membrane-bending problem is the molecules can drive membranes to bend derives in part from the bilayer protein fraction embedded within the bilayer. Far from being inert vesicle couple model of Sheetz and Singer12. These authors recognized that tight passengers, cargo proteins represent major constituents of vesicles10 that coupling between the two leaflets of a lipid bilayer engenders curvature, probably contribute a significant energy barrier to membrane bending. As whereby expanding or compressing one side of the membrane would cargo concentration increases and membrane curvature progresses, the cause the other side to experience the opposite effect (i.e. compression surface area available to each protein decreases on the concave lumenal or expansion). The increased abundance of molecules and the increased 1020 NATURE CELL BIOLOGY VOLUME 15 | NUMBER 9 | SEPTEMBER 2013 © 2013 Macmillan Publishers Limited. All rights reserved REVIEW rate of collisions within or adjacent to one leaflet of the membrane causes ab the area of the leaflet to increase relative to the opposite leaflet, leading to Reduced steric pressure membrane curvature away from the source of increased steric pressure Cytosol (Fig. 2b). The phenomenon of curvature driven

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