| Structural highlights
Function
[SORT_MOUSE] Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface. Required for protein transport from the Golgi apparatus to the lysosomes by a pathway that is independent of the mannose-6-phosphate receptor (M6PR). Also required for protein transport from the Golgi apparatus to the endosomes. Promotes neuronal apoptosis by mediating endocytosis of the proapoptotic precursor forms of BDNF (proBDNF) and NGFB (proNGFB). Also acts as a receptor for neurotensin. May promote mineralization of the extracellular matrix during osteogenic differentiation by scavenging extracellular LPL. Probably required in adipocytes for the formation of specialized storage vesicles containing the glucose transporter SLC2A4/GLUT4 (GLUT4 storage vesicles, or GSVs). These vesicles provide a stable pool of SLC2A4 and confer increased responsiveness to insulin. May also mediate transport from the endoplasmic reticulum to the Golgi.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Low pH-induced ligand release and receptor recycling are important steps for endocytosis. The transmembrane protein sortilin, a beta-propeller containing endocytosis receptor, internalizes a diverse set of ligands with roles in cell differentiation and homeostasis. The molecular mechanisms of pH-mediated ligand release and sortilin recycling are unresolved. Here we present crystal structures that show the sortilin luminal segment (s-sortilin) undergoes a conformational change and dimerizes at low pH. The conformational change, within all three sortilin luminal domains, provides an altered surface and the dimers sterically shield a large interface while bringing the two s-sortilin C-termini into close proximity. Biophysical and cell-based assays show that members of two different ligand families, (pro)neurotrophins and neurotensin, preferentially bind the sortilin monomer. This indicates that sortilin dimerization and conformational change discharges ligands and triggers recycling. More generally, this work may reveal a double mechanism for low pH-induced ligand release by endocytosis receptors.
Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release.,Leloup N, Lossl P, Meijer DH, Brennich M, Heck AJR, Thies-Weesie DME, Janssen BJC Nat Commun. 2017 Nov 22;8(1):1708. doi: 10.1038/s41467-017-01485-5. PMID:29167428[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hashiramoto M, James DE. Characterization of insulin-responsive GLUT4 storage vesicles isolated from 3T3-L1 adipocytes. Mol Cell Biol. 2000 Jan;20(1):416-27. PMID:10594043
- ↑ Zeng J, Hassan AJ, Morales CR. Study of the mouse sortilin gene: Effects of its transient silencing by RNA interference in TM4 Sertoli cells. Mol Reprod Dev. 2004 Aug;68(4):469-75. doi: 10.1002/mrd.20097. PMID:15236332 doi:http://dx.doi.org/10.1002/mrd.20097
- ↑ Hassan AJ, Zeng J, Ni X, Morales CR. The trafficking of prosaposin (SGP-1) and GM2AP to the lysosomes of TM4 Sertoli cells is mediated by sortilin and monomeric adaptor proteins. Mol Reprod Dev. 2004 Aug;68(4):476-83. doi: 10.1002/mrd.20096. PMID:15236333 doi:http://dx.doi.org/10.1002/mrd.20096
- ↑ Dicou E, Vincent JP, Mazella J. Neurotensin receptor-3/sortilin mediates neurotensin-induced cytokine/chemokine expression in a murine microglial cell line. J Neurosci Res. 2004 Oct 1;78(1):92-9. PMID:15372498 doi:http://dx.doi.org/10.1002/jnr.20231
- ↑ Shi J, Kandror KV. Sortilin is essential and sufficient for the formation of Glut4 storage vesicles in 3T3-L1 adipocytes. Dev Cell. 2005 Jul;9(1):99-108. doi: 10.1016/j.devcel.2005.04.004. PMID:15992544 doi:http://dx.doi.org/10.1016/j.devcel.2005.04.004
- ↑ Kim T, Hempstead BL. NRH2 is a trafficking switch to regulate sortilin localization and permit proneurotrophin-induced cell death. EMBO J. 2009 Jun 3;28(11):1612-23. doi: 10.1038/emboj.2009.118. Epub 2009 Apr 30. PMID:19407813 doi:http://dx.doi.org/10.1038/emboj.2009.118
- ↑ Vaegter CB, Jansen P, Fjorback AW, Glerup S, Skeldal S, Kjolby M, Richner M, Erdmann B, Nyengaard JR, Tessarollo L, Lewin GR, Willnow TE, Chao MV, Nykjaer A. Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat Neurosci. 2011 Jan;14(1):54-61. doi: 10.1038/nn.2689. Epub 2010 Nov 21. PMID:21102451 doi:http://dx.doi.org/10.1038/nn.2689
- ↑ Leloup N, Lossl P, Meijer DH, Brennich M, Heck AJR, Thies-Weesie DME, Janssen BJC. Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release. Nat Commun. 2017 Nov 22;8(1):1708. doi: 10.1038/s41467-017-01485-5. PMID:29167428 doi:http://dx.doi.org/10.1038/s41467-017-01485-5
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