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| Crystal structure of the N-glycosylated human Gpc-1 core protein (PDB entry 4ACR). Cartoon diagram of Gpc-1 in which the body of the structure is coloured light blue, the N-terminal helix and loop in dark blue and the C-terminal helix in red. Important loops (L1:L3) and all of the α-helices (α1:α14) are labelled. The seven disulphide bonds common to all glypicans are indicated in yellow. The assignment of different lobes in the Gpc-1 structure (Svensson et al., 2011) is displayed on the bottom line. |
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Description | The glypican-1 gene codes for a protein of 558 amino acids with a predicted molecular weight of 62 kDa. It is a cell surface, lipid-raft-associated heparan sulfate proteoglycan (HSPG), composed of a glycosylphosphatidylinositol (GPI)-anchored core protein substituted with a three chains of heparan sulfate near its C-terminus. It shares, along with all other glypicans, an N-terminal secretory signal, heparan sulfate attachment sites, 14 evolutionary conserved cysteine residues and hydrophobic domain near the C-terminus for the addition of the glycosylphosphatidylinositol (GPI) anchor. Also, the glypican-1 core protein contains two N-glycosylation sites at Asn79 & Asn116, which are found to be invariably occupied. The N-linked glycans at these sites affect Gpc-1 protein expression and heparan sulfate substitution. Nevertheless the protein is folded correctly even in the absence of N-linked glycans (Svensson et al., 2011). Recently, the structure of C-terminally truncated human N-glycosylated Gpc-1 core protein was determined at 2.55 Å resolution (Svensson et al., 2012; Awad et al., 2013), which revealed a highly extended, cylindrical (dimensions 120 x 30 x 30 Å), stable all-α-helical fold. Its structural similarity to the Dally-like protein from Drosophila (Kim et al., 2011) confirmed a conserved overall fold for the glypican family. The Gpc-1 structure consists of 14 α-helices (α1- α14) and three major loops (L1-L3). The extended helix α2 (83Å) traverses the whole protein, carrying two N-linked glycans close to its ends. The Gpc-1 structure revealed the complete arrangement of the 14 Cys residues conserved across the glypican family, in 7 disulfide bonds, 6 of them located near the molecule N terminus at a region termed "Cys-rich lobe". This lobe is followed by a region forms the heart of the structure called the "central lobe". This lobe is stabilized by evolutionary conserved hydrophobic centers. The last region of the Gpc-1 molecule is termed the "protease site lobe" because of the presence of a protease site in this part. No additional electron density was observed in the electron density maps from crystals of non-truncated glypican-1 containing the HS attachment region near the C-terminus, which suggests that this part is highly disordered. This extended long C terminus (50 residues) might thus give the core protein a freedom in its orientation when Gpc-1 is anchored to the cell membrane (Svensson et al., 2012). |
Expression | GPC1 is expressed mainly in the central nervous system (CNS) and skeletal system during development but also in many other tissues in the adult. |
Localisation | GPC1 is a cell surface HSPG that can be internalized via a caveolin-1 associated pathway. GPC1 undergoes a recycling from cell surface to endosomes and back to the cell surface via Golgi. During recycling, the HS chains of GPC1 are degraded by heparanase and further on by a novel copper, nitric oxide and vitamin C-dependent deaminative cleavage. New HS chains are synthesized on the stubs remaining on the core protein (Cheng et al., 2002; Fransson and Mani, 2007). |
Function | Many of the functions of GPC1 are dependent on the HS side chains, which are capable of binding and/or activating and/or transporting a variety of growth factors (FGF2), cytokines, enzymes, viral proteins, and polyamines. It is known that both the core protein and the HS chains of GPC1 are important for brain function, as knock-out of GPC1 gene expression results in reduction of brain size by 30% (Jen et al., 2009) and errors in HS metabolism result in neurodegeneration and mental retardation accompanied by accumulation of amyloid β in human brain (Ohmi et al., 2011). A role for GPC1 in axonal guidance and regeneration via Slit has been proposed (Bloechlinger et al., 2004; Lau and Margolis, 2010). Several studies indicate involvement of Gpc1 in prion conversion and scrapie infection (Löfgren et al., 2008; Taylor et al., 2009; Hooper, 2011). |
Homology | GPC1 belongs to the glypican family. To date, six different glypicans have been identified in vertebrates (GPC1, GPC2, GPC3, GPC4, GPC5, and GPC6), two in Drosophila melanogaster (Dally and Dally-like protein), two in C. elegans (Gpn-1 and Lon-2) and one in zebrafish (knypek). Based on sequence comparisons, vertebrate glypicans fall into two subfamilies: glypicans 1, 2, 4, 6 and glypicans 3 and 5, with approximately 25% amino acid identity between the groups. |
Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells. |
Aikawa T, Whipple CA, Lopez ME, Gunn J, Young A, Lander AD, Korc M. |
J Clin Invest. 2008 Jan;118(1):89-99. |
PMID 18064304 |
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Improvements in the order, isotropy and electron density of glypican-1 crystals by controlled dehydration. |
Awad W, Svensson Birkedal G, Thunnissen MM, Mani K, Logan DT. |
Acta Crystallogr D Biol Crystallogr. 2013 Dec;69(Pt 12):2524-33. doi: 10.1107/S0907444913025250. Epub 2013 Nov 19. |
PMID 24311593 |
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Dynamic changes in glypican-1 expression in dorsal root ganglion neurons after peripheral and central axonal injury. |
Bloechlinger S, Karchewski LA, Woolf CJ. |
Eur J Neurosci. 2004 Mar;19(5):1119-32. |
PMID 15016071 |
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The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-Nitric Oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo. |
Cappai R, Cheng F, Ciccotosto GD, Needham BE, Masters CL, Multhaup G, Fransson LA, Mani K. |
J Biol Chem. 2005 Apr 8;280(14):13913-20. Epub 2005 Jan 27. |
PMID 15677459 |
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Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, nitric oxide (NO)-catalyzed degradation. |
Cheng F, Cappai R, Ciccotosto GD, Svensson G, Multhaup G, Fransson LA, Mani K. |
J Biol Chem. 2011 Aug 5;286(31):27559-72. doi: 10.1074/jbc.M111.243345. Epub 2011 Jun 3. |
PMID 21642435 |
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Copper-dependent co-internalization of the prion protein and glypican-1. |
Cheng F, Lindqvist J, Haigh CL, Brown DR, Mani K. |
J Neurochem. 2006 Sep;98(5):1445-57. |
PMID 16923158 |
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Nitric oxide-dependent processing of heparan sulfate in recycling S-nitrosylated glypican-1 takes place in caveolin-1-containing endosomes. |
Cheng F, Mani K, van den Born J, Ding K, Belting M, Fransson LA. |
J Biol Chem. 2002 Nov 15;277(46):44431-9. Epub 2002 Sep 10. |
PMID 12226079 |
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Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells. |
Ding K, Lopez-Burks M, Sanchez-Duran JA, Korc M, Lander AD. |
J Cell Biol. 2005 Nov 21;171(4):729-38. Epub 2005 Nov 14. |
PMID 16286510 |
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Novel aspects of vitamin C: how important is glypican-1 recycling? |
Fransson LA, Mani K. |
Trends Mol Med. 2007 Apr;13(4):143-9. Epub 2007 Mar 6. |
PMID 17344097 |
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Glypican-1 facilitates prion conversion in lipid rafts. |
Hooper NM. |
J Neurochem. 2011 Mar;116(5):721-5. doi: 10.1111/j.1471-4159.2010.06936.x. (REVIEW) |
PMID 20681952 |
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Glypican-1 controls brain size through regulation of fibroblast growth factor signaling in early neurogenesis. |
Jen YH, Musacchio M, Lander AD. |
Neural Dev. 2009 Sep 4;4:33. doi: 10.1186/1749-8104-4-33. |
PMID 19732411 |
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Correlation of glypican-1 expression with TGF-beta, BMP, and activin receptors in pancreatic ductal adenocarcinoma. |
Kayed H, Kleeff J, Keleg S, Jiang X, Penzel R, Giese T, Zentgraf H, Buchler MW, Korc M, Friess H. |
Int J Oncol. 2006 Nov;29(5):1139-48. |
PMID 17016645 |
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Structure of the protein core of the glypican Dally-like and localization of a region important for hedgehog signaling. |
Kim MS, Saunders AM, Hamaoka BY, Beachy PA, Leahy DJ. |
Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13112-7. doi: 10.1073/pnas.1109877108. Epub 2011 Jul 26. |
PMID 21828006 |
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Inhibitors of slit protein interactions with the heparan sulphate proteoglycan glypican-1: potential agents for the treatment of spinal cord injury. |
Lau E, Margolis RU. |
Clin Exp Pharmacol Physiol. 2010 Apr;37(4):417-21. doi: 10.1111/j.1440-1681.2009.05318.x. Epub 2009 Oct 16. |
PMID 19843094 |
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Involvement of glypican-1 autoprocessing in scrapie infection. |
Lofgren K, Cheng F, Fransson LA, Bedecs K, Mani K. |
Eur J Neurosci. 2008 Sep;28(5):964-72. doi: 10.1111/j.1460-9568.2008.06386.x. Epub 2008 Aug 20. |
PMID 18717736 |
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Defective nitric oxide-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts. |
Mani K1, Cheng F, Fransson LA. |
Glycobiology. 2006 Aug;16(8):711-8. Epub 2006 Apr 27. |
PMID 16645004 |
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Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. |
Matsuda K, Maruyama H, Guo F, Kleeff J, Itakura J, Matsumoto Y, Lander AD, Korc M. |
Cancer Res. 2001 Jul 15;61(14):5562-9. |
PMID 11454708 |
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Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contributed by glial cells. |
O'Callaghan P, Sandwall E, Li JP, Yu H, Ravid R, Guan ZZ, van Kuppevelt TH, Nilsson LN, Ingelsson M, Hyman BT, Kalimo H, Lindahl U, Lannfelt L, Zhang X. |
Brain Pathol. 2008 Oct;18(4):548-61. doi: 10.1111/j.1750-3639.2008.00152.x. Epub 2008 Apr 11. |
PMID 18422760 |
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Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B. |
Ohmi K, Zhao HZ, Neufeld EF. |
PLoS One. 2011;6(11):e27461. doi: 10.1371/journal.pone.0027461. Epub 2011 Nov 9. |
PMID 22096577 |
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Heparan sulfate mediates amyloid-beta internalization and cytotoxicity. |
Sandwall E, O'Callaghan P, Zhang X, Lindahl U, Lannfelt L, Li JP. |
Glycobiology. 2010 May;20(5):533-41. doi: 10.1093/glycob/cwp205. Epub 2010 Jan 5. |
PMID 20053627 |
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Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells. |
Su G, Meyer K, Nandini CD, Qiao D, Salamat S, Friedl A. |
Am J Pathol. 2006 Jun;168(6):2014-26. |
PMID 16723715 |
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Crystal structure of N-glycosylated human glypican-1 core protein: structure of two loops evolutionarily conserved in vertebrate glypican-1. |
Svensson G, Awad W, Hakansson M, Mani K, Logan DT. |
J Biol Chem. 2012 Apr 20;287(17):14040-51. doi: 10.1074/jbc.M111.322487. Epub 2012 Feb 20. |
PMID 22351761 |
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Glypican-1 mediates both prion protein lipid raft association and disease isoform formation. |
Taylor DR, Whitehouse IJ, Hooper NM. |
PLoS Pathog. 2009 Nov;5(11):e1000666. doi: 10.1371/journal.ppat.1000666. Epub 2009 Nov 20. |
PMID 19936054 |
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Amyloid beta induces cellular relocalization and production of agrin and glypican-1. |
Timmer NM, van Horssen J, Otte-Holler I, Wilhelmus MM, David G, van Beers J, de Waal RM, Verbeek MM. |
Brain Res. 2009 Mar 13;1260:38-46. doi: 10.1016/j.brainres.2008.12.063. Epub 2009 Jan 7. |
PMID 19166823 |
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Glypican-1 as an Abeta binding HSPG in the human brain: its localization in DIG domains and possible roles in the pathogenesis of Alzheimer's disease. |
Watanabe N, Araki W, Chui DH, Makifuchi T, Ihara Y, Tabira T. |
FASEB J. 2004 Jun;18(9):1013-5. Epub 2004 Apr 14. |
PMID 15084524 |
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A KrasG12D-driven genetic mouse model of pancreatic cancer requires glypican-1 for efficient proliferation and angiogenesis. |
Whipple CA, Young AL, Korc M. |
Oncogene. 2012 May 17;31(20):2535-44. doi: 10.1038/onc.2011.430. Epub 2011 Sep 26. |
PMID 21996748 |
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Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain. |
Zhang X, Wang B, O'Callaghan P, Hjertstrom E, Jia J, Gong F, Zcharia E, Nilsson LN, Lannfelt L, Vlodavsky I, Lindahl U, Li JP. |
Acta Neuropathol. 2012 Oct;124(4):465-78. doi: 10.1007/s00401-012-0997-1. Epub 2012 Jun 13. |
PMID 22692572 |
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Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains. |
van Horssen J, Otte-Holler I, David G, Maat-Schieman ML, van den Heuvel LP, Wesseling P, de Waal RM, Verbeek MM. |
Acta Neuropathol. 2001 Dec;102(6):604-14. |
PMID 11761721 |
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