Abstract
Polymerisation of clathrin is a key process that underlies clathrin-mediated endocytosis. Clathrin-coated vesicles are responsible for cell internalization of external substances required for normal homeostasis and life –sustaining activity. There are several hypotheses describing formation of closed clathrin structures. According to one of the proposed mechanisms cage formation may start from a flat lattice buildup on the cellular membrane, which is later transformed into a curved structure. Creation of the curved surface requires rearrangement of the lattice, induced by additional molecular mechanisms. Different potential mechanisms require a modeling framework that can be easily modified to compare between them. We created an extendable rule-based model that describes polymerisation of clathrin molecules and various scenarios of cage formation. Using Global Sensitivity Analysis (GSA) we obtained parameter sets describing clathrin pentagon closure and the emergence/production and closure of large-size clathrin cages/vesicles. We were able to demonstrate that the model can reproduce budding of the clathrin cage from an initial flat array.
Highlights
Clathrin is the major protein component of clathrin–mediated endocytosis (CME)[1,2]
Within the cell clathrin exists in a form of trimers, consisting of three clathrin molecules, where individual clathrin monomers are referred to as “legs”
Triskelia formation itself does not seem to be influenced by a loss of light chain molecules[11], but regulatory control of vesicle formation and cargo selection have been proposed
Summary
Clathrin is the major protein component of clathrin–mediated endocytosis (CME)[1,2]. Due to its particular shape and (auto-) polymerization capacity, clathrin is believed to induce the cell membrane to adopt a vesicular shape. Within the cell clathrin exists in a form of trimers (triskelia), consisting of three clathrin molecules (three heavy and three light chains respectively), where individual clathrin monomers are referred to as “legs”. In a normal biological context, hexagonal and pentagonal shapes are among the most frequently observed[12,13]. Specific combinations of these shapes induce the formation of the typical vesicle closed spherical structure. Since its discovery in 197514, significant attention has been focused on the mechanism of clathrin polymerisation It was highlighted in[1] that understanding CME is not possible without proper knowledge of its key process, the clathrin cage formation. It was experimentally shown that clathrin self-assembles following pH decrease from 8 to 6.515 or under bivalent cation administration[16], to obtain biologically realistic vesicle shapes the participation of external regulatory proteins is likely critical[1]
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