Abstract
Membrane remodeling is a critical process for many membrane trafficking events, including clathrin-mediated endocytosis. Several molecular mechanisms for protein-induced membrane curvature have been described in some detail. Contrary, the effect that the physico-chemical properties of the membrane have on these processes is far less well understood. Here, we show that the membrane binding and curvature-inducing ENTH domain of epsin1 is regulated by phosphatidylserine (PS). ENTH binds to membranes in a PI(4,5)P2-dependent manner but only induces curvature in the presence of PS. On PS-containing membranes, the ENTH domain forms rigid homo-oligomers and assembles into clusters. Membrane binding and membrane remodeling can be separated by structure-to-function mutants. Such oligomerization mutants bind to membranes but do not show membrane remodeling activity. In vivo, they are not able to rescue defects in epidermal growth factor receptor (EGFR) endocytosis in epsin knock-down cells. Together, these data show that the membrane lipid composition is important for the regulation of protein-dependent membrane deformation during clathrin-mediated endocytosis.
Highlights
Clathrin-mediated endocytosis (CME) is a special form of vesicle budding from the plasma membrane that capitalizes on a formation of clathrin lattices around maturing buds
As we identified a mutant with a clear phenotype in in vitro investigations, we asked if oligomer-dependent membrane remodeling is of physiological importance in clathrin-mediated endocytosis
We present the identification of a lipid-dependency for protein-induced membrane remodeling during CME for the ENTH domain of epsin1
Summary
Clathrin-mediated endocytosis (CME) is a special form of vesicle budding from the plasma membrane that capitalizes on a formation of clathrin lattices around maturing buds. In this orchestrated and highly dynamic process some 50 proteins come together to internalize receptors, extracellular. Over the years a number of proteins with the ability to deform membranes were identified to be important in this process [3, 4]. One family of these proteins are epsins. Despite the necessity of PI(4,5)P2 to bind the ENTH domain, almost nothing is known about the involvement of the membrane lipid composition in protein-dependent membrane deformation
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