Adaptor protein complexes and intracellular transport

Abstract

The AP (adaptor protein) complexes are heterotetrameric protein complexes that mediate intracellular membrane trafficking along endocytic and secretory transport pathways. There are five different AP complexes: AP-1, AP-2 and AP-3 are clathrin-associated complexes; whereas AP-4 and AP-5 are not. These five AP complexes localize to different intracellular compartments and mediate membrane trafficking in distinct pathways. They recognize and concentrate cargo proteins into vesicular carriers that mediate transport from a donor membrane to a target organellar membrane. AP complexes play important roles in maintaining the normal physiological function of eukaryotic cells. Dysfunction of AP complexes has been implicated in a variety of inherited disorders, including: MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis and keratodermia) syndrome, Fried syndrome, HPS (Hermansky-Pudlak syndrome) and HSP (hereditary spastic paraplegia).

Figure 1. Localization and trafficking of AP complexes

AP-1 is localized to TGN and REs, and mediates bidirectional transport between them. AP-1 also mediates basolateral sorting in epithelial cells. AP-2 plays a role in clathrin-dependent endocytosis from the plasma membrane. AP-3 is localized to endosomes, and responsible for the LRO biogenesis. AP-4 is localized to TGN, and mediates vesicle trafficking from TGN to endosomes or basolateral plasma membrane. AP-5 is localized to late endosomes, and its function is largely unknown.

Figure 2. Structures of AP complexes

(A) Diagrams of heterotetrameric AP complexes. All AP complexes consist of core, hinge, and ear domains, except AP5 that lacks hinge domain. Core domains are responsible for the cargo protein binding and membrane localization. Hinge and ear domains are important to the interaction with coat proteins and regulatory/accessory proteins. (B) Locked and open structure of AP-1 core complexes. In the locked state, the cargo-binding sites of AP-1 are hindered by two large subunits (γ and β1). In the presence of Arf1 binding, AP-1 undergoes a large conformational change to the open state. In the open state, both [D/E]XXXL[L/I] and YXXØ-binding sites are exposed and ready to bind to corresponding cargo proteins (yellowish circles). Structures are generated from PDB code 1W63 (locked state) [53], and 4HMY (open state) [15].