Bending "On the Rocks"--A Cocktail of Biophysical Modules to Build Endocytic Pathways

Abstract

Numerous biological processes rely on endocytosis. The construction of endocytic pits is achieved by a bewildering complexity of biochemical factors that function in clathrin-dependent and -independent pathways. In this review, we argue that this complexity can be conceptualized by a deceptively small number of physical principles that fall into two broad categories: passive mechanisms, such as asymmetric transbilayer stress, scaffolding, line tension, and crowding, and active mechanisms driven by mechanochemical enzymes and/or cytoskeleton. We illustrate how the functional identity of biochemical modules depends on system parameters such as local protein density on membranes, thus explaining some of the controversy in the field. Different modules frequently operate in parallel in the same step and often are shared by apparently divergent uptake processes. The emergence of a novel endocytic classification system may thus be envisioned in which functional modules are the elementary bricks.

Endocytic Accessory Factors and Regulation of Clathrin-Mediated Endocytosis

“…For mammalian cells, it is well established that membrane scission is controlled by the large GTPase dynamin and, because dynamin is perhaps one of the most extensively studied EAPs, rather than tackle the extensive literature, we will limit our discussion to a handful of recent key findings and refer the interested reader to several recent and extensive reviews Ramachandran 2011;Schmid and Frolov 2011;Ferguson and De Camilli 2012;Morlot and Roux 2013; see also Johannes et al 2014).…”

Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

“…Release of a coated vesicle thus requires that dynamin enable the neck of a coated pit to reorganize into a transition state that leads to pinching, although the mechanism remains unknown (for recent reviews, see Schmid and Frolov 2011;Chappie and Dyda 2013;Morlot and Roux 2013;Johannes et al 2014). Acute inhibition of the dynamin GTPase activity with the compound dynasore causes accumulation of coated pits at two stages-pits with a fully constricted neck ("omega"-shaped cross sections) (Heuser 1980;Macia et al 2006) as might be expected from the properties of dynamin collars and helices on lipid tubes in vitro, and pits just at the point at which a constriction is beginning to form ("U"-shaped cross sections).…”

“…The physical properties of lipid bilayers imply a substantial energy cost for invagination and budding of a vesicle. To divide a single, spherical phospholipid bilayer into two smaller vesicles requires 350 kT ( 250 kcal/mol), with the details depending on such factors as the intrinsic curvature imparted to the bilayer by its specific lipid composition (see Johannes et al 2014). In a cell, rapid lateral diffusion of lipids means that some of the energy can be supplied by other processes, even at some distance-for example, processes that use or remove lipids for which the relevant curvature of the invagination is particularly unfavorable.…”

Lipid Sorting and Multivesicular Endosome Biogenesis

“…Animal cells take up solutes, nutrients, ligands, and components of the plasma membrane via multiple endocytic pathways, which all merge in common early endosomes (Mayor and Pagano 2007;Doherty and McMahon 2009;Donaldson et al 2013;Johannes et al 2013;Kirchhausen et al 2013;Merrifield and Kaksonen 2013). There, cargo can be sorted to different cellular destinations, including the plasma membrane, the trans-Golgi network (TGN), or late endosomes.…”