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.

Sequence-dependent trafficking and activity of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

“…Dileucine-based motifs in the cytosolic tails of transmembrane proteins bind to the prototypical AP-2 clathrin adaptor complex that associates with the cytosolic face of the plasma membrane to mediate endocytosis (Kelly et al, 2008), with a strong requirement for inositol phospholipids (Sanger et al, 2019). Adaptor protein (AP) complexes such as AP-2 are particularly important for polarized sorting in neuronal cells, given their extreme morphological asymmetry (Bonifacino, 2014), while AP dysfunction underlies a range of neurological pathologies (Guardia et al, 2018;Sanger et al, 2019). Further studies are needed to define the exact sequence of this putative LI-based sorting motif and its possible interaction with the AP-2 complex.…”

“…6A). Canonical dileucine motifs are acidic and contain six amino acids (consensus [D/E]xxxL[L/I]), and mediate endocytosis of transmembrane proteins via direct interaction with the clathrin adaptor complex AP-2 (Bonifacino and Traub, 2003;Cullen and Steinberg, 2018;Guardia et al, 2018;Kelly et al, 2008). Mutating Leu-553 to a serine residue in GDE2(ΔC560) or GDE2-FL [which may have a more prominent effect than a leucine to alanine mutation in this case (Denzer et al, 1997)] led to strongly disrupted internalization and enhanced accumulation on the cell surface (Fig.…”

The Potential Role of the ZIKV NS5 Nuclear Spherical-Shell Structures in Cell Type-Specific Host Immune Modulation during ZIKV Infection

“…While the crucial role of NLS sequences in the nuclear transport process of flavivirus NS5 proteins has been demonstrated through site-specific mutagenesis, additional cellular processes such as post-translational modifications (PTMs) have also been shown to play a role in the regulation of the subcellular localization of cellular proteins [52]. In fact, correct localization of cellular proteins has also been shown to be important for proper function of these proteins [53,54]. In the case of flavivirus NS5 proteins, YFV [16] and DENV NS5 [43,55] are phosphorylated and localized into the nucleus, with a hyperphosphorylated form of DENV NS5 being associated with nuclear localization [19].…”

Golgipathies in Neurodevelopment: A New View of Old Defects

“…AP4-deficiency syndrome is caused by a mutation in a subunit of another of the five adaptor protein complexes, AP1-5, mentioned above (reviewed in [66]). AP4-deficiency syndrome, which includes a very large range of phenotypes, may be included among the large number of hereditary spastic paraplegias [107].…”