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. 2017 Apr;74(8):1475-1483.
doi: 10.1007/s00018-016-2410-z. Epub 2016 Nov 10.

Sorting Receptor SORLA: Cellular Mechanisms and Implications for Disease

Free PMC article

Sorting Receptor SORLA: Cellular Mechanisms and Implications for Disease

Vanessa Schmidt et al. Cell Mol Life Sci. .
Free PMC article


Sorting-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs cargo proteins, such as kinases, phosphatases, and signaling receptors, to their correct location within the cell. The activity of SORLA assures proper function of cells and tissues, and receptor dysfunction is the underlying cause of common human malignancies, including Alzheimer's disease, atherosclerosis, and obesity. Here, we discuss the molecular mechanisms that govern sorting of SORLA and its cargo in multiple cell types, and why genetic defects in this receptor results in devastating diseases.

Keywords: Alzheimer’s disease; GGA; Obesity; Protein sorting; Retromer; VPS10P domain receptors.


Fig. 1
Fig. 1
Structural organization of SORLA. a Organization of the SORLA polypeptide is shown, indicating the main structural elements and their documented functions. The VPS10P domain and the cluster of complement-type repeats serve as major ligand-binding sites in the luminal receptor domain. The β-propeller interacts with the molecular chaperone MESD to facilitate folding of the receptor polypeptide, and it may be involved in pH-dependent release of bound ligands in acidic endosomal compartments. b Amino-acid sequence of the cytoplasmic receptor tail highlighting three main binding motifs for cytosolic adaptors, termed FANSHY, the acidic motif (DDLGEDDED), and the GGA-binding site (DDVPMV). GGA, Golgi-localizing, γ-adaptin ear homology domain, ARF-interacting protein; MESD, mesodermal development deletion interval; VPS10P, vacuolar protein sorting 10 proteins. a adapted from [43]
Fig. 2
Fig. 2
Intracellular trafficking path for SORLA. Nascent SORLA is an inactive pro-receptor (pro-SORLA) that is activated by proteolytic removal of an amino-terminal pro-peptide in the TGN, resulting in transfer of the active receptor (SORLA) through the constitutive secretory pathway to the cell surface. Some receptor molecules at the cell surface are subjected to ectodomain shedding, resulting in release of the extracellular receptor domain. Ectodomain shedding disrupts the ability of SORLA to act as a sorting receptor, but may serve to produce a soluble receptor fragment termed soluble (s)SORLA that acts as a signaling molecule. Still, most SORLA molecules at the cell surface remain intact and undergo clathrin-dependent endocytosis facilitated by the clathrin adaptor protein (AP) 2. The bulk of internalized receptors move from endosomes back to the TGN to continuously shuttle between TGN and endosomal compartments thereafter. Adaptors GGA1 and GGA2 guide anterograde movement of SORLA from the TGN to endosomes, whereas PACS1 and the retromer complex facilitate retrograde sorting from endosomes back to the Golgi. AP1 may be involved in bi-directional sorting. As alternative routes, SORLA may sort from endosomes to the cell surface (aided by adaptor SNX27) or to lysosomes (aided by GGA3). Figure adapted from [43]. AP, adaptor protein; GGA, Golgi-localizing, γ-adaptin ear homology domain, ARF-interacting protein; PACS1, phosphofurin acidic cluster sorting protein 1; SNX27, sorting nexin family member 27

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