Figure 3.

Pathways of receptor endocytosis. Endocytosis involves the capture of transmembrane proteins and their extracellular ligands into cytoplasmic vesicles that are pinched off from the plasma membrane. The best-studied pathway of receptor internalization is mediated by clathrin-coated pits. These are small areas of the plasma membrane that are covered on the cytoplasmic surface with clathrin triskelions, which comprise three clathrin heavy chains and three clathrin light chains assembled into a polyhedral clathrin lattice. Receptors are recruited to clathrin-coated pits by directly interacting with the clathrin coat adaptor complex AP2 or by binding to other adaptor proteins, which in turn interact with the clathrin heavy chain and/or AP2. Clathrin-coated pits invaginate inwards with the help of several accessory proteins and pinch off to form clathrin-coated vesicles in a process that requires the GTPase dynamin. Several clathrin-independent pathways of endocytosis also exist, although the precise mechanisms and structural components involved in these pathways are not well understood. Endocytic vesicles derived from both clathrin-dependent and -independent endocytosis fuse with early endosomes. Endosomal trafficking is controlled by several Rab proteins, which are small GTP-binding proteins of the Ras superfamily. Each GTP-bound Rab protein resides in a particular type of endosome and functions by recruiting specific effector proteins. Following their internalization into early RAB5-containing endosomes, receptors can rapidly recycle back to the plasma membrane by a RAB4-dependent mechanism, traffic to the recycling compartment that contains RAB11A, or remain in endosomes, which mature into multivesicular bodies (MVBs) and late endosomes. MVBs are defined by the presence of intraluminal vesicles (ILVs), which are formed by inward membrane invagination involving endosomal sorting complex required for transport (ESCRT) complexes. Early-to-late endosome maturation involves the acquisition of RAB7 and the removal of endosomal components that are capable of, and necessary for, recycling. In the MVBs, cargo destined for degradation is incorporated into ILVs. Fusion of late endosomes and MVBs with lysosomes carrying proteolytic enzymes results in cargo degradation. Reproduced, with permission, from Ref. [145].