Sortilin (neurotensin receptor 3, glycoprotein 95) is a 95 kDa Type I transmembrane monomeric glycoprotein that is one of five known members of the mammalian vacuolar protein sorting 10p domain (Vps10pD) family of sorting receptors (1, 2).Human preprosortilin is processed by signal sequence cleavage followed by propeptide cleavage at a furin recognition site. The cationic propeptide exhibits pHdependent high affinity binding that blocks the Sortilin ligand binding site both preand postcleavage (3). The extracellular/luminal sequence comprises the Vps10p domain, including 10 conserved cysteines (10 CC) essential for ligand binding (2). The cytoplasmic domain sorting motifs confer all trafficking during synthesis, targeting to lysosomes, endocytosis and Golgiendosome transport; as little as 10% may be found on the cell surface (4). Mature human Sortilin shares 91% aa identity with mouse and rat Sortilin and 93% aa identity with dog. During murine development, sortilin is mainly expressed in the nervous system (5) where it is a receptor for neuropeptides including neurotensin, nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) (6 9). ProNGF(or the NGF propeptide alone) binds sortilin with much higher affinity (Kd ~5 8nM) than does mature NGF (Kd ~90 nM). The complex of sortilin,proNGF and the receptor p75ntr results in endocytosis of proNGF and induction of apoptosis(7). Similar results have been obtained with proBDNF and BDNF (8, 9). Sortilin is expressed in other tissues including testis, skeletal muscle and fat (1,10). It is essential and sufficient for biogenesis of Glut4 storage vesicles necessary for insulin responsiveness in adipocytes (10). Sortilin also binds lipoprotein lipase (11), apoE (2) and RAP (1,11). Binding is competitive, indicating that although unrelated, targets likely bind the same site.
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2. Westergaard, U.B. et al. (2004) J. Biol. Chem. 279:50221.
3. Petersen, C.M. et al. (1998) EMBO J. 18:595.
4. Nielsen, M.S. et al. (2001) EMBO J. 20:2180.
5. HermansBorgmeyer, I. et al. (1999) Mol. Brain Res. 65:216.
6. Mazella, J. et al. (1998) J. Biol. Chem. 273:26273.
7. Nykjaer, A et al. (2004) Nature 427:843.
8. Teng, H.K. et al. (2005) J. Neurosci. 25:5455.
9. Chen, ZY et al. (2004) J. Neurosci. 25:6156.
10. Shi, J and K.V. Kandror (2005) Dev. Cell 9:99.
11. Nielsen, M. S. et al. (1999) J. Biol. Chem. 274:8832.
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