Pathway variability, coat stiffening and mechanical adaptation during clathrin-mediated endocytosis

Abstract

Clathrin assemblies in cells can persist as flat plaques, abort after partial invagination, or close into clathrin-coated vesicles, but the determinants of these different fates remain unresolved. To investigate the stochastic and complex dynamics of clathrin assemblies, we have developed a kinetic Monte Carlo simulation framework that couples individual clathrin agents to an adaptive continuum membrane. In this hybrid discrete-continuum description, the effective coat bending rigidity and the preferred coat curvature emerge during growth, rather than being prescribed as material parameters. Once connected, curved lattices stiffen from molecular bending modes to coat-level rigidities, because curvature changes require increased stretching or compression, while newly incorporated triskelia hardcode a history-dependent preferred curvature. An analytical theory for non-Euclidean elasticity identifies the relevant internal variables and predicts growth laws that are validated by the simulations. The same microscopic assembly rules yield flat, stalled, and closed coats through two sequential gates in the effective membrane-coat energy landscape. Comparisons with experimentally observed coat geometries and nanodissection-induced curvature changes agree with our theoretical predictions without any fitting parameters. The clathrin coat thus emerges as an adaptive assembly with prestress and memory, whose fate and material parameters reflect the environment in which it has been growing.