Abstract
In eukaryotic cells, the internalization of extracellular cargo via the endocytic machinery is an important regulatory process required for many essential cellular functions. The role of cooperative protein-protein and protein-membrane interactions in the ubiquitous endocytic pathway in mammalian cells, namely the clathrin-dependent endocytosis, remains unresolved. We employ the Helfrich membrane Hamiltonian together with surface evolution methodology to address how the shapes and energetics of vesicular-bud formation in a planar membrane are stabilized by presence of the clathrin-coat assembly. Our results identify a unique dual role for the tubulating protein epsin: multiple epsins localized spatially and orientationally collectively play the role of a curvature inducing capsid; in addition, epsin serves the role of an adapter in binding the clathrin coat to the membrane. Our results also suggest an important role for the clathrin lattice, namely in the spatial- and orientational-templating of epsins. We suggest that there exists a critical size of the coat above which a vesicular bud with a constricted neck resembling a mature vesicle is stabilized. Based on the observed strong dependence of the vesicle diameter on the bending rigidity, we suggest that the variability in bending stiffness due to variations in membrane composition with cell type can explain the experimentally observed variability on the size of clathrin-coated vesicles, which typically range 50–100 nm. Our model also provides estimates for the number of epsins involved in stabilizing a coated vesicle, and without any direct fitting reproduces the experimentally observed shapes of vesicular intermediates as well as their probability distributions quantitatively, in wildtype as well as CLAP IgG injected neuronal cell experiments. We have presented a minimal mesoscale model which quantitatively explains several experimental observations on the process of vesicle nucleation induced by the clathrin-coated assembly prior to vesicle scission in clathrin dependent endocytosis.
Highlights
The cellular process of endocytosis is important in the biological regulation of trafficking in cells, as well as impacts the technology of targeted drug delivery in nanomedicine [1,2,3,4,5,6,7]
The model describes a crucial step in the intracellular endocytic trafficking mechanisms, i.e., active transport mechanisms mediated through budding of the cell membrane orchestrated by protein-interaction networks
The particular application to endocytosis explored here can help discern pathological cellular trafficking fates of receptors implicated in a variety of biomedical conditions such as cancer, as well as impact the technology of targeted drug delivery in nanomedicine
Summary
The cellular process of endocytosis is important in the biological regulation of trafficking in cells, as well as impacts the technology of targeted drug delivery in nanomedicine [1,2,3,4,5,6,7]. Several experimental [8] as well as theoretical [9,10,11] treatments have addressed mechanisms in endocytosis, yet the role of cooperative protein-protein and protein-membrane interactions in the ubiquitous endocytic pathway in mammalian cells, namely clathrin-dependent endocytosis (CDE), remains unresolved. A sequence of molecular events in CDE is responsible for the recruitment of adaptor protein 2 (AP-2), accessory proteins such as epsin, AP180, Eps, Dynamin, etc., and the scaffolding protein clathrin to the plasma membrane [8]. The accessory proteins such as epsin are implicated in membrane bending [12]. Even though actin is believed to play an important role in the endocytosis process in S. cerevisiae (yeast), in mammalian cells, actin repression, at best, has a small effect on endocytosis [14]
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