biostudies-literatureGuo SKNational Institute of General Medical SciencesNIGMS NIH HHSNational Institute of Child Health and Human Developmente1009969https://www.ebi.ac.uk/biostudies/studies/S-EPMC8979592biostudies-literatureUnknown18(3)Clathrin-coated structures must assemble on cell membranes to internalize receptors, with the clathrin protein only linked to the membrane via adaptor proteins. These structures can grow surprisingly large, containing over 20 clathrin, yet they often fail to form productive vesicles, instead aborting and disassembling. We show that clathrin structures of this size can both form and disassemble spontaneously when adaptor protein availability is low, despite high abundance of clathrin. Here, we combine recent in vitro kinetic measurements with microscopic reaction-diffusion simulations and theory to differentiate mechanisms of stable vs unstable clathrin assembly on membranes. While in vitro conditions drive assembly of robust, stable lattices, we show that concentrations, geometry, and dimePLoS computational biologyLarge self-assembled clathrin lattices spontaneously disassemble without sufficient adaptor proteins.PMC8979592R35 GM133644R35GM133644Intramural Research ProgramSodt AJJohnson MEGuo SKfalseLarge self-assembled clathrin lattices spontaneously disassemble without sufficient adaptor proteins.Clathrin-coated structures must assemble on cell membranes to internalize receptors, with the clathrin protein only linked to the membrane via adaptor proteins. These structures can grow surprisingly large, containing over 20 clathrin, yet they often fail to form productive vesicles, instead aborting and disassembling. We show that clathrin structures of this size can both form and disassemble spontaneously when adaptor protein availability is low, despite high abundance of clathrin. Here, we combine recent in vitro kinetic measurements with microscopic reaction-diffusion simulations and theory to differentiate mechanisms of stable vs unstable clathrin assembly on membranes. While in vitro conditions drive assembly of robust, stable lattices, we show that concentrations, geometry, and dime2022-01-01T00:00:00Z2022 Mar2026-03-16T08:02:14.096Z2025-04-05T15:59:35.511ZS-EPMC89795923531269210.1371/journal.pcbi.1009969