4msl

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Crystal structure of the Vps10p domain of human sortilin/NTS3 in complex with AF40431

Structural highlights

4msl is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:2ET, BMA, MAN, NAG, PG4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SORT_HUMAN Note=A common polymorphism located in a non-coding region between CELSR2 and PSRC1 alters a CEBP transcription factor binding site and is responsible for changes in hepatic expression of SORT1. Altered SORT1 expression in liver affects low density lipoprotein cholesterol levels in plasma and is associated with susceptibility to myocardial infarction.

Function

SORT_HUMAN 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] [8] [9] [10]

Publication Abstract from PubMed

Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7 A resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming pi-stacking with a phenylalanine.

Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex.,Andersen JL, Schroder TJ, Christensen S, Strandbygard D, Pallesen LT, Garcia-Alai MM, Lindberg S, Langgard M, Eskildsen JC, David L, Tagmose L, Simonsen KB, Maltas PJ, Ronn LC, de Jong IE, Malik IJ, Egebjerg J, Karlsson JJ, Uppalanchi S, Sakumudi DR, Eradi P, Watson SP, Thirup S Acta Crystallogr D Biol Crystallogr. 2014 Feb;70(Pt 2):451-60. doi:, 10.1107/S1399004713030149. Epub 2014 Jan 29. PMID:24531479[11]

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

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Citations
2 reviews cite this structure
Sortilin and Its Multiple Roles in Cardiovascular and Metabolic Diseases.
Goettsch et al. (2018)
1 more
13 other articles
No citations found

See Also

References

  1. ↑ Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM. Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase. J Biol Chem. 1999 Mar 26;274(13):8832-6. PMID:10085125
  2. ↑ Nielsen MS, Madsen P, Christensen EI, Nykjaer A, Gliemann J, Kasper D, Pohlmann R, Petersen CM. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J. 2001 May 1;20(9):2180-90. PMID:11331584 doi:10.1093/emboj/20.9.2180
  3. ↑ Takatsu H, Katoh Y, Shiba Y, Nakayama K. Golgi-localizing, gamma-adaptin ear homology domain, ADP-ribosylation factor-binding (GGA) proteins interact with acidic dileucine sequences within the cytoplasmic domains of sorting receptors through their Vps27p/Hrs/STAM (VHS) domains. J Biol Chem. 2001 Jul 27;276(30):28541-5. Epub 2001 Jun 4. PMID:11390366 doi:10.1074/jbc.C100218200
  4. ↑ Maeda S, Nobukuni T, Shimo-Onoda K, Hayashi K, Yone K, Komiya S, Inoue I. Sortilin is upregulated during osteoblastic differentiation of mesenchymal stem cells and promotes extracellular matrix mineralization. J Cell Physiol. 2002 Oct;193(1):73-9. PMID:12209882 doi:10.1002/jcp.10151
  5. ↑ Lefrancois S, Zeng J, Hassan AJ, Canuel M, Morales CR. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. EMBO J. 2003 Dec 15;22(24):6430-7. PMID:14657016 doi:10.1093/emboj/cdg629
  6. ↑ Martin S, Vincent JP, Mazella J. Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neurosci. 2003 Feb 15;23(4):1198-205. PMID:12598608
  7. ↑ Morinville A, Martin S, Lavallee M, Vincent JP, Beaudet A, Mazella J. Internalization and trafficking of neurotensin via NTS3 receptors in HT29 cells. Int J Biochem Cell Biol. 2004 Nov;36(11):2153-68. PMID:15313463 doi:10.1016/j.biocel.2004.04.013
  8. ↑ Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004 Feb 26;427(6977):843-8. PMID:14985763 doi:10.1038/nature02319
  9. ↑ Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005 Jun 1;25(22):5455-63. PMID:15930396 doi:25/22/5455
  10. ↑ Chen ZY, Ieraci A, Teng H, Dall H, Meng CX, Herrera DG, Nykjaer A, Hempstead BL, Lee FS. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J Neurosci. 2005 Jun 29;25(26):6156-66. PMID:15987945 doi:25/26/6156
  11. ↑ Andersen JL, Schroder TJ, Christensen S, Strandbygard D, Pallesen LT, Garcia-Alai MM, Lindberg S, Langgard M, Eskildsen JC, David L, Tagmose L, Simonsen KB, Maltas PJ, Ronn LC, de Jong IE, Malik IJ, Egebjerg J, Karlsson JJ, Uppalanchi S, Sakumudi DR, Eradi P, Watson SP, Thirup S. Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex. Acta Crystallogr D Biol Crystallogr. 2014 Feb;70(Pt 2):451-60. doi:, 10.1107/S1399004713030149. Epub 2014 Jan 29. PMID:24531479 doi:http://dx.doi.org/10.1107/S1399004713030149

Contents


PDB ID 4msl

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