Neuronal functions of adaptor complexes involved in protein sorting

Abstract

Selective transport of transmembrane proteins to different intracellular compartments often involves the recognition of sorting signals in the cytosolic domains of the proteins by components of membrane coats. Some of these coats have as their key components a family of heterotetrameric adaptor protein (AP) complexes named AP-1 through AP-5. AP complexes play important roles in all cells, but their functions are most critical in neurons because of the extreme compartmental complexity of these cells. Accordingly, various diseases caused by mutations in AP subunit genes exhibit a range of neurological abnormalities as their most salient features. In this article, we discuss the properties of the different AP complexes, with a focus on their roles in neuronal physiology and pathology.

Figure 1

Neuronal processes mediated by AP complexes. A. Schematic representation of a neuron with its domains and subdomains. AIS: axon initial segment. B. AP complexes involved in polarized sorting from the soma. AP-1 and AP-4 are shown to sort proteins from the TGN and/or endosomes to the somatodendritic (SD) domain [8,9,10,11•]. In contrast, AP-3 sorts proteins to the axon [11•]. C. AP-2 mediates endocytosis of receptors at the post-synaptic terminal [30,31,32,33•]. RE: recycling endosome. D. AP complexes involved in sorting at the pre-synaptic terminal. AP-1 mediates retrieval of escaped somatodendritic proteins to the soma [9]. AP-2 is shown to participate in endocytosis of synaptic vesicle (SV) proteins from the plasma membrane and biogenesis of SV from endosomes [18,19,20,21,64,29]. AP-3 contributes to SV biogenesis from synaptic vesicle precursors (SVP) [40,41]. E. Non-canonical function of AP-2 in coupling axonal autophagosomes containing BDNF-activated TrkB receptors to dynein-dynactin for retrograde transport towards the soma [34].

Figure 2

Properties of AP complexes. A. Schematic representation of AP complexes indicating their subunit composition and domain organization. B. Architecture of a generic coat. Docking factors recruit AP complexes to the membrane, after which the AP complexes recruit scaffolding proteins and concentrate transmembrane cargos by virtue of interactions with sorting signals in the cytosolic domains of the cargos. C. Clathrin-coated pits and vesicles (arrows) at a pre-synaptic terminal [16] ©1973 Heuser, John et al. Journal of Cell Biology. 57(2):315-344. doi:10.1083/jcb.57.2.315.