Stochastic Model of Clathrin-Coated Pit Assembly

Abstract

In recent years, fluorescence microscopy has enabled researchers to observe the dynamics of clathrin-coated pit (CCP) assembly in real time. The assembly dynamics of CCPs shows striking heterogeneity. Some CCPs are long-lived (productive CCPs); they bind cargo and grow in size to form clathrin-coated vesicles. In contrast, other CCPs (abortive CCPs) are relatively short-lived and disassemble well before reaching vesicle size. Within both populations there is significant variance in CCP lifetime. We propose a stochastic biophysical model that links these observations with the energetics of CCPs and kinetics of their assembly. We show that without cargo, CCP assembly faces a high energy barrier that is difficult to overcome. As a consequence, CCPs without cargo are almost always abortive. We suggest a mechanism by which cargo binding stabilizes CCPs and facilitates their growth. The lifetime distribution of abortive pits calculated from our model agrees well with published experimental data. We also estimate the lifetimes of productive CCPs and show that the stochastic nature of CCP assembly plays a crucial role in causing their observed wide distribution.

The big and intricate dreams of little organelles: Embracing complexity in the study of membrane traffic

“…48,70,[76][77][78][79][80][81][82][83][84][85][86] In addition, specific CCP properties have been linked to cargo receptor content. 78,85 This type of data has allowed the construction of computational models to describe CCP assembly and scission, 87 from which now emerges the synergism between predictions made by these computational models and experimental testing that are at the core of systems biology.…”

Clathrin polymerization exhibits high mechano-geometric sensitivity

“…These experimental studies are complimented by the modeling work by Walani et al which suggests that an increase in tension should lead to smaller clathrin coat in order to match experimentally observed shapes observed in mammalian and yeast cells 17 . In addition, stochastic models have given fundamental insights into clathrin self-assembly 18,19 and dynamic rearrangements in clathrin lattices 20–22 . In particular, curvature generation by indentation has been shown to promote solid to fluid phase transition in a planar clathrin lattice 21 .…”

Unraveling protein–protein interactions in clathrin assemblies via atomic force spectroscopy

“…This complex energy-dependent process, which is not fully understood, drives the internalization of extracellular nutrients and membrane-bound receptors. To dissect this complex process, investigators have reconstituted functional clathrin-containing structures in vitro (26) and in simulations and modeling (27-32). …”