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Conformational Switches Regulate Clathrin Mediated Endocytosis

Abstract

Clathrin mediated endocytosis is a fundamental cellular process used to regulate the response of cells to their environment. It has been usurped as a means for pathogens to enter cells. Clathrin mediated endocytosis is driven by the polymerization of clathrin into a polyhedral lattice. Lattice formation is critical for stabilization of membranes and organization of the protein machinery used to form a budding vesicle. Clathrin has a unique three legged structure. The legs interweave to form the lattice. Regulation of the process of lattice assembly has been observationally described for over twenty years. The mechanisms of regulation are only now being defined.

The clathrin endocytic machinery is closely associated with the actin cytoskeleton. This may allow the force of actin polymerization to be harnessed for coated vesicle formation or actin may play an additional stabilizing role during endocytosis. The interaction between clathrin and actin machineries is becoming an increasingly important research area. The details of the link between clathrin and actin are not yet determined.

To help define the mechanisms involved in forming clathrin coated vesicles and linking clathrin to the actin cytoskeleton biochemical and structural studies were undertaken. The first structure of the regulatory clathrin light chain suggested a conformational switch regulated clathrin assembly. Structural and biochemical work on the huntingtin interacting proteins again suggested a conformational switch regulates the link between clathrin and actin.

This work suggests a general mechanism of numerous conformational switches being flipped to regulated clathrin mediated endocytosis.

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