Proteopedia

5znn

Crystal structure of ligand-free form of the Vps10 ectodomain of SortilinCrystal structure of ligand-free form of the Vps10 ectodomain of Sortilin

Structural highlights

5znn is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.448Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Sortilin is a multifunctional sorting receptor involved in cytokine production in immune cells. To understand the mechanism of Sortilin-mediated cytokine trafficking, we determined the 2.45-A structure of the dimerized Sortilin ectodomain (sSortilin or the Vps10-domain) crystallized at acidic pH. Substantial conformational changes upon dimerization lead to the intermolecular hydrophobic interaction between the conserved E455 and F137. Analysis of the electrostatic surface and size-exclusion chromatography revealed that sSortilin dimerization occurs due to an increase in hydrophobic interactions at the neutral dimer interface at acidic pH. The N682-attached N-glycan in the vicinity of the dimer interface implies its involvement in the dimerization. The disruption of Sortilin dimerization by mutations impairs efficient interferon-alpha secretion from cells. These results suggest the functional importance of Sortilin dimerization in cytokine trafficking.

Crystal structure of the ligand-free form of the Vps10 ectodomain of dimerized Sortilin at acidic pH.,Yabe-Wada T, Matsuba S, Unno M, Onai N FEBS Lett. 2018 Jul 4. doi: 10.1002/1873-3468.13181. PMID:29972886[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ Yabe-Wada T, Matsuba S, Unno M, Onai N. Crystal structure of the ligand-free form of the Vps10 ectodomain of dimerized Sortilin at acidic pH. FEBS Lett. 2018 Jul 4. doi: 10.1002/1873-3468.13181. PMID:29972886 doi:http://dx.doi.org/10.1002/1873-3468.13181

5znn, resolution 2.45Å

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