Minimal mesoscale model for protein-mediated vesiculation in clathrin-dependent endocytosis
| Autor: | Jonathan Nukpezah, Neeraj Jagdish Agrawal, Ravi Radhakrishnan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Biophysics/Theory and Simulation
Epsin Endocytic cycle Biophysics Adaptor Protein Complex 2 Coated vesicle Biology 01 natural sciences Clathrin coat Clathrin Models Biological Exocytosis Physics/Interdisciplinary Physics 03 medical and health sciences Cellular and Molecular Neuroscience Cell Biology/Membranes and Sorting 0103 physical sciences Genetics Animals Particle Size 010306 general physics Molecular Biology lcsh:QH301-705.5 Ecology Evolution Behavior and Systematics 030304 developmental biology Mammals 0303 health sciences Ecology Vesicle Computational Biology Clathrin-Coated Vesicles Endocytosis Cell biology Biomechanical Phenomena Adaptor Proteins Vesicular Transport Eukaryotic Cells Computational Theory and Mathematics lcsh:Biology (General) Modeling and Simulation biology.protein Thermodynamics Vesicle scission Research Article |
| Zdroj: | PLoS Computational Biology, Vol 6, Iss 9 (2010) PLoS Computational Biology |
| ISSN: | 1553-7358 |
| Popis: | 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. Author Summary Cell membranes and membrane-based organelles actively mediate several intracellular signaling and trafficking decisions. A growing number of applications rely on cooperative interactions between molecular assemblies and membranes. Yet, the studies of membrane-based and membrane-mediated signaling are not considered core aspects of systems biology. While a coherent and complete description of cell membrane-mediated signaling is not always possible by experimental methods, multiscale modeling and simulation approaches can provide valuable insights at microscopic and mesoscopic scales. Here, we present a quantitative model for describing how cell-membrane topologies are actively mediated and manipulated by intracellular protein assemblies. Specifically, 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 proposed theory and modeling approach is expected to create avenues for many novel applications in systems biology, pharmacology, and nanobiotechnology. 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. |
| Databáze: | OpenAIRE |
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