A cost-benefit analysis of the physical mechanisms of membrane curvature

Abstract

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.

Figure 1. Cellular sites of membrane curvature

The membranes of eukaryotic cells display many instances of membrane curvature, some of which are dynamic (e.g. transport vesicles, endosomal tubules, viral buds) and others more static (e.g. nuclear pores, cilia, ER tubules, 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, mitochondrial ATP synthase). COPI structure reprinted from Faini et al. , copyright 2004, with permission from AAAS. COPII structure reprinted from Stagg et al , clathrin structure reprinted from Fotin et al , and retromer model reprinted from Hierro et al . Septin model reprinted from Tanaka-Takiguchi et al. , copyright 2009, with permission from Elsevier. ESCRT structure reprinted from Effantin et al., copyright 2013, with permission from Wiley.

Figure 2. Steric effects during membrane curvature

(A) As a vesicle bud forms, the decrease in surface area on the lumenal face restricts mobility of lumenal protein mass, increasing the local steric pressure to resist bending. Simultaneously, the cytoplasmic surface area increases, reducing steric pressure on this face, necessitating increased force at the cytoplasmic face to maintain bending. (B) Complete asymmetry of lumenally oriented proteins during budding could create negative spontaneous curvature. (C) Conversely to B, if lumenally oriented proteins oligomerize, their affinity for each other and the membrane could drive mending bending in the appropriate direction. (D) Recruitment of cargo adaptors to nascent budding sites could create local curvature by entropic means and reverse cargo resistance.

Figure 3. Energetics of coated vesicle formation

Compiling quantitative data and models from the recent literature, we estimate the energetic budget responsible for formation of coated vesicles of variable size. (A) Energetic costs of membrane bending including bending rigidity and tension. (B) Energetic costs of cargo confinement in the vesicle lumen^,, (C) Energy contributions by drivers of membrane bending including actin polymerization, clathrin coat assembly, confinement of accessory proteins (AP) beneath coats, and hydrophobic insertions. The colors of each icon correspond to their energetic contributions delineated in the plot. (D) Comparison of energetic costs with energetic drivers during coated vesicle formation. Drivers (actin, clathrin coats and APs) are blue and creating cost-creating cargo are mauve. See Box 1 for further description of these energy estimates.