Modeling order and disorder in clathrin protein assemblies
Abstract/Contents
- Abstract
- Many biological components such as proteins self-assemble into large structures that perform vital functions. Understanding the processes by which these structures form and their collective response to environmental stimuli provides valuable insight into biological strategies for organization and transport. Also, the ability of these components to self-assemble has been explored as a promising route in fabricating nanoscale technologies with broad applications including energy, medicine and advanced electronics. One such protein that robustly assembles in vivo and in vitro is clathrin, which is the primary constituent of the coat surrounding vesicles that are internalized during clathrin-mediated endocytosis (CME). In this work, we use computational models to explore the physical driving forces that dictate formation, reorganization and destruction of ordered clathrin assemblies. To capture relevant physical behavior on reasonable computational timescales, we employ a simplified mesoscale representation of clathrin as an elastic three-legged pinwheel, which can be coupled to an elastic sheet membrane model. This enables the in silico formation of cages in solution and lattices on membranes, similar to those observed in experiments. We first use this model to explain the distinct dynamic assembly pathways that clathrin adopts when assembling in solution at different acidities. At pH above its isoelectric point, clathrin forms cages through piecewise, ordered assembly that progresses monotonically in size. Below its isoelectric point, the components form large disordered masses over the first hour that slowly reconfigure into cages resembling those in the more basic solutions. Through our simulations, we demonstrate that these alternate pathways are likely driven by non-specific interaction energies, which are known to be highly dependent on acidity. Biological assembly of clathrin happens exclusively on membrane surfaces. Our model elucidates the role that membrane properties have on associated clathrin lattices. By altering the tension of our simulated membranes, we demonstrate that the suppression of membrane fluctuations stabilizes large, flat, crystalline lattices, while large fluctuations cause these structures to melt into a fluid, disordered phase. These observations are in accordance with existing theories of two-dimensional melting on flexible surfaces. Our results also explain the experimental observations of ordered clathrin "plaques" on cell surfaces that are adhered to solid substrates, while no plaques are found on unadhered cell surfaces. Finally, we study the response of clathrin lattices to large membrane deformations under varying degrees of tension by indenting the flexible membranes with spherical model particles. Similar deformations occur as a matter of course during CME. We observe that these indentations result in localized defect formation near the regions of high curvature, and occasionally lead to bulk-scale fluidization of the entire surrounding lattice. The indentation-driven transition between crystalline and fluid lattices depends on the membrane tension as well as the elasticity of the clathrin subunits themselves. These results suggest a previously unexplored physical mechanism within the cell, in which the dissolution of plaques or the transition from plaques to more physiologically functional structures may be induced by the wrapping of cargo.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Cordella, Nicholas |
|---|---|
| Associated with | Stanford University, Department of Chemical Engineering. |
| Primary advisor | Spakowitz, Andrew James |
| Thesis advisor | Spakowitz, Andrew James |
| Thesis advisor | Melosh, Nicholas A |
| Thesis advisor | Shaqfeh, Eric S. G. (Eric Stefan Garrido) |
| Advisor | Melosh, Nicholas A |
| Advisor | Shaqfeh, Eric S. G. (Eric Stefan Garrido) |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Nicholas Cordella. |
|---|---|
| Note | Submitted to the Department of Chemical Engineering. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Nicholas Cordella
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...