Clathrin

Clathrin is a mantle protein involved in the invagination of cell membranes and the formation of vesicles (especially in clathrin-mediated endocytosis). After strangulation, the clathrin of the clathrin-coated vesicles is removed in an ATP-dependent manner ("uncoating" by the uncoating ATPase).

Clathrin is an exceptionally structured protein. It is a hexamer consisting of three heavy and three light subunits, of which there are two isoforms each. The subunits have a three-legged structure (triskelion). This enables them to form a two-dimensional network consisting of hexagons and pentagons. The importance of these macromolecules was unknown for a long time until it was discovered that at physiological pH, the heavy chains spontaneously assembled into cages, ball-shaped vesicles. This is prevented in the presence of the light chain. They thus seem to modulate the assembly of clathrin into such vesicle structures.

Since clathrin itself cannot bind to membranes, it requires the help of adapter proteins. For this purpose, the terminal domain, which mediates the binding to these proteins, extends far into the centre of a clathrin cage (Figure 1-3 B). In contrast, the light chains are located on the outside (Figure 1-3 C) of a cage, which makes them easily accessible for regulatory proteins.

These clathrin cages have diameters ranging from 50 to 100 nm and are covered by a scaffold of mostly 12 penta- and 8 hexagons of a total of 36 triple skeletons of clathrin. This fibrous protein consists of a heavy chain (180,000 daltons [Da]) and a light chain (35,000 to 40,000 Da). In addition, the 900 amino acid dynamin, which can bind and hydrolyze GTP, is also found in the vesicle coat. Clathrin does not itself bind to membranes, but via different adaptor protein complexes (AP complexes). These AP complexes dock to the heavy chains of clathrin. In addition, the AP complexes bind to membrane lipids and membrane proteins and thus mediate the binding of clathrin to membranes. AP-2 mediates the formation of "clathrin-coated vesicles" (CCV) at the plasma membrane. AP-1 mediates CCV formation at the trans-Golgi network, the last compartment of the protein synthesis apparatus in the secretory transport pathway. AP4 is the only representative of the heterotetrameric adaptor complexes and does not have a typical clathrin box sequence. Therefore, the involvement of AP4 in the formation of CCVs is controversial. The clathrin envelope is rapidly lost within the cell. An endosome is formed which fuses with membrane vesicles from the Golgi apparatus and forms larger edosomal compartments. Receptors are separated from the ligands and transported back to the cell surface in membrane vesicles (receptor recycling). The ligands enter a multivesicular body (endolysosome). Hydrolases are transported from the Golgi apparatus in clathrin-enveloped vesicles to the endolysosome.

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