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| | ==Crystal structure of full-length glypican-1 core protein after controlled crystal dehydration to 87% relative humidity== | | ==Crystal structure of full-length glypican-1 core protein after controlled crystal dehydration to 87% relative humidity== |
| - | <StructureSection load='4ywt' size='340' side='right' caption='[[4ywt]], [[Resolution|resolution]] 2.38Å' scene=''> | + | <StructureSection load='4ywt' size='340' side='right'caption='[[4ywt]], [[Resolution|resolution]] 2.38Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ywt]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YWT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YWT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ywt]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YWT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YWT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.38Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ad7|4ad7]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ywt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ywt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ywt RCSB], [http://www.ebi.ac.uk/pdbsum/4ywt PDBsum]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ywt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ywt OCA], [https://pdbe.org/4ywt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ywt RCSB], [https://www.ebi.ac.uk/pdbsum/4ywt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ywt ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GPC1_HUMAN GPC1_HUMAN]] Biliary atresia. Associates (via the heparan sulfate side chains) with fibrillar APP-beta amyloid peptides in primitive and classic amyloid plaques and may be involved in the deposition of these senile plaques in the Alzheimer disease (AD) brain. Misprocessing of GPC1 is found in fibroblasts of patients with Niemann-Pick Type C1 disease. This is due to the defective deaminative degradation of heparan sulfate chains. | + | [https://www.uniprot.org/uniprot/GPC1_HUMAN GPC1_HUMAN] Biliary atresia. Associates (via the heparan sulfate side chains) with fibrillar APP-beta amyloid peptides in primitive and classic amyloid plaques and may be involved in the deposition of these senile plaques in the Alzheimer disease (AD) brain. Misprocessing of GPC1 is found in fibroblasts of patients with Niemann-Pick Type C1 disease. This is due to the defective deaminative degradation of heparan sulfate chains. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GPC1_HUMAN GPC1_HUMAN]] Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination (By similarity). May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling.<ref>PMID:19936054</ref> <ref>PMID:21642435</ref> | + | [https://www.uniprot.org/uniprot/GPC1_HUMAN GPC1_HUMAN] Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination (By similarity). May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling.<ref>PMID:19936054</ref> <ref>PMID:21642435</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | The use of controlled dehydration for improvement of protein crystal diffraction quality is increasing in popularity, although there are still relatively few documented examples of success. A study has been carried out to establish whether controlled dehydration could be used to improve the anisotropy of crystals of the core protein of the human proteoglycan glypican-1. Crystals were subjected to controlled dehydration using the HC1 device. The optimal protocol for dehydration was developed by careful investigation of the following parameters: dehydration rate, final relative humidity and total incubation time Tinc. Of these, the most important was shown to be Tinc. After dehydration using the optimal protocol the crystals showed significantly reduced anisotropy and improved electron density, allowing the building of previously disordered parts of the structure.
| + | Glypicans are multifunctional cell surface proteoglycans involved in several important cellular signalling pathways. Glypican-1 (Gpc1) is the predominant heparan sulphate (HS) proteoglycan in the developing and adult human brain. The two N-linked glycans and the C-terminal domain that attaches the core protein to the cell membrane are not resolved in the Gpc1 crystal structure. Therefore we have studied Gpc1 using crystallography, small-angle X-ray scattering and chromatographic approaches to elucidate the composition, structure and function of the N-glycans and the C-terminus, and also the topology of Gpc1 with respect to the membrane. The C-terminus is shown to be highly flexible in solution, but it orients the core protein transverse to the membrane, directing a surface evolutionarily conserved in Gpc1 orthologues towards the membrane, where it may interact with signalling molecules and/or membrane receptors on the cell surface, or even the enzymes involved in HS substitution in the Golgi apparatus Furthermore, the N-glycans are shown to extend the protein stability and lifetime by protection against proteolysis and aggregation. |
| | | | |
| - | 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<ref>PMID:24311593</ref>
| + | Structural aspects of N-glycosylations and the C-terminal region in human glypican-1.,Awad W, Adamczyk B, Ornros J, Karlsson NG, Mani K, Logan DT J Biol Chem. 2015 Jul 22. pii: jbc.M115.660878. PMID:26203194<ref>PMID:26203194</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4ywt" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Awad, W]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Logan, D T]] | + | [[Category: Large Structures]] |
| - | [[Category: Mani, K]] | + | [[Category: Awad W]] |
| - | [[Category: Controlled dehydration]] | + | [[Category: Logan DT]] |
| - | [[Category: Diffraction quality]] | + | [[Category: Mani K]] |
| - | [[Category: Glypican-1]]
| + | |
| - | [[Category: Hc1b]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| Structural highlights
Disease
GPC1_HUMAN Biliary atresia. Associates (via the heparan sulfate side chains) with fibrillar APP-beta amyloid peptides in primitive and classic amyloid plaques and may be involved in the deposition of these senile plaques in the Alzheimer disease (AD) brain. Misprocessing of GPC1 is found in fibroblasts of patients with Niemann-Pick Type C1 disease. This is due to the defective deaminative degradation of heparan sulfate chains.
Function
GPC1_HUMAN Cell surface proteoglycan that bears heparan sulfate. Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination (By similarity). May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling.[1] [2]
Publication Abstract from PubMed
Glypicans are multifunctional cell surface proteoglycans involved in several important cellular signalling pathways. Glypican-1 (Gpc1) is the predominant heparan sulphate (HS) proteoglycan in the developing and adult human brain. The two N-linked glycans and the C-terminal domain that attaches the core protein to the cell membrane are not resolved in the Gpc1 crystal structure. Therefore we have studied Gpc1 using crystallography, small-angle X-ray scattering and chromatographic approaches to elucidate the composition, structure and function of the N-glycans and the C-terminus, and also the topology of Gpc1 with respect to the membrane. The C-terminus is shown to be highly flexible in solution, but it orients the core protein transverse to the membrane, directing a surface evolutionarily conserved in Gpc1 orthologues towards the membrane, where it may interact with signalling molecules and/or membrane receptors on the cell surface, or even the enzymes involved in HS substitution in the Golgi apparatus Furthermore, the N-glycans are shown to extend the protein stability and lifetime by protection against proteolysis and aggregation.
Structural aspects of N-glycosylations and the C-terminal region in human glypican-1.,Awad W, Adamczyk B, Ornros J, Karlsson NG, Mani K, Logan DT J Biol Chem. 2015 Jul 22. pii: jbc.M115.660878. PMID:26203194[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Taylor DR, Whitehouse IJ, Hooper NM. Glypican-1 mediates both prion protein lipid raft association and disease isoform formation. PLoS Pathog. 2009 Nov;5(11):e1000666. doi: 10.1371/journal.ppat.1000666. Epub, 2009 Nov 20. PMID:19936054 doi:10.1371/journal.ppat.1000666
- ↑ Cheng F, Cappai R, Ciccotosto GD, Svensson G, Multhaup G, Fransson LA, Mani K. 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. J Biol Chem. 2011 Aug 5;286(31):27559-72. doi: 10.1074/jbc.M111.243345. Epub 2011, Jun 3. PMID:21642435 doi:http://dx.doi.org/10.1074/jbc.M111.243345
- ↑ Awad W, Adamczyk B, Ornros J, Karlsson NG, Mani K, Logan DT. Structural aspects of N-glycosylations and the C-terminal region in human glypican-1. J Biol Chem. 2015 Jul 22. pii: jbc.M115.660878. PMID:26203194 doi:http://dx.doi.org/10.1074/jbc.M115.660878
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