Dynamically tuning the membrane lipid composition can control macromolecular assembly

Clathrin-mediated endocytosis (CME) is an essential process for transport

into the cell, requiring hundreds of protein components to assemble into

large macromolecular structures on the cell membrane. The composition of

the plasma membrane is critical for initiating assembly, as proteins bind

specifically only to subpopulations of lipids. Two opposing lipid-modifying

enzymes can dynamically tune these lipid populations, and it is not known to

what extent these enzymes help promote or inhibit protein recruitment at

specific places and times. This dynamical complexity of CME makes it not

only an interesting process to study for its own sake, but for the potential to

reveal general principles for controlling self-assembly on a 2D surface.

However, this very complexity and the fast time scales make CME difficult to

interrogate in vivo with sufficient resolution, thus the relationships between

environmental variables and the dynamics of clathrin-coated vesicle

formation are yet to be fully characterized. Here, we use computational

modeling to quantify how macromolecular self-assembly can be dynamically

tuned via the composition of the plasma membrane and protein

stoichiometry. Our models solve differential equations with the structure-

resolved reaction-diffusion software NERDSS, as well as non-spatial ordinary

differential equations that are amenable to efficient parameter optimization

and sensitivity analysis. We found a novel mechanism for biochemical

feedback loops allowing for switch-like lipid remodeling and oscillatory

behavior. We discuss how the principles established here for controlling

membrane composition are informative for a broader range of processes

across biological systems.