|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Mouse galactocerebrosidase in complex with saposin A== | | ==Mouse galactocerebrosidase in complex with saposin A== |
| - | <StructureSection load='5nxb' size='340' side='right' caption='[[5nxb]], [[Resolution|resolution]] 3.60Å' scene=''> | + | <StructureSection load='5nxb' size='340' side='right'caption='[[5nxb]], [[Resolution|resolution]] 3.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5nxb]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5n8k 5n8k]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NXB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NXB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5nxb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5n8k 5n8k]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NXB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NXB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <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]] 3.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Galc ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), Psap, Sgp1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Galactosylceramidase Galactosylceramidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.46 3.2.1.46] </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=5nxb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nxb OCA], [https://pdbe.org/5nxb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nxb RCSB], [https://www.ebi.ac.uk/pdbsum/5nxb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nxb ProSAT]</span></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=5nxb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nxb OCA], [http://pdbe.org/5nxb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nxb RCSB], [http://www.ebi.ac.uk/pdbsum/5nxb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nxb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE]] Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin. | + | [https://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE] Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE]] Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.<ref>PMID:8769874</ref> [[http://www.uniprot.org/uniprot/SAP_MOUSE SAP_MOUSE]] Prosaposin: Behaves as a myelinotrophic and neurotrophic factor, these effects are mediated by its G-protein-coupled receptors, GPR37 and GPR37L1, undergoing ligand-mediated internalization followed by ERK phosphorylation signaling.<ref>PMID:23690594</ref> Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate.[UniProtKB:P07602] Saposin-B stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases.[UniProtKB:P07602] Saposin-D is a specific sphingomyelin phosphodiesterase activator (EC 3.1.4.12).[UniProtKB:P07602] Saposins are specific low-molecular mass non-enzymic proteins, they participate in the lysosomal degradation of sphingolipids, which takes place by the sequential action of specific hydrolases.[UniProtKB:P07602] | + | [https://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE] Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.<ref>PMID:8769874</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 22: |
Line 21: |
| | </div> | | </div> |
| | <div class="pdbe-citations 5nxb" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5nxb" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Galactosylceramidase|Galactosylceramidase]] |
| | + | *[[Saposin|Saposin]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Galactosylceramidase]] | + | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Deane, J E]] | + | [[Category: Deane JE]] |
| - | [[Category: Graham, S C]] | + | [[Category: Graham SC]] |
| - | [[Category: Hill, C H]] | + | [[Category: Hill CH]] |
| - | [[Category: Galactocerebroside]]
| + | |
| - | [[Category: Galactosylceramide]]
| + | |
| - | [[Category: Galc]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Krabbe disease]]
| + | |
| - | [[Category: Sapa]]
| + | |
| Structural highlights
Disease
GALC_MOUSE Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin.
Function
GALC_MOUSE Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.[1]
Publication Abstract from PubMed
Sphingolipids are essential components of cellular membranes and defects in their synthesis or degradation cause severe human diseases. The efficient degradation of sphingolipids in the lysosome requires lipid-binding saposin proteins and hydrolytic enzymes. The glycosphingolipid galactocerebroside is the primary lipid component of the myelin sheath and is degraded by the hydrolase beta-galactocerebrosidase (GALC). This enzyme requires the saposin SapA for lipid processing and defects in either of these proteins causes a severe neurodegenerative disorder, Krabbe disease. Here we present the structure of a glycosphingolipid-processing complex, revealing how SapA and GALC form a heterotetramer with an open channel connecting the enzyme active site to the SapA hydrophobic cavity. This structure defines how a soluble hydrolase can cleave the polar glycosyl headgroups of these essential lipids from their hydrophobic ceramide tails. Furthermore, the molecular details of this interaction provide an illustration for how specificity of saposin binding to hydrolases is encoded.
The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure.,Hill CH, Cook GM, Spratley SJ, Fawke S, Graham SC, Deane JE Nat Commun. 2018 Jan 11;9(1):151. doi: 10.1038/s41467-017-02361-y. PMID:29323104[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sakai N, Inui K, Tatsumi N, Fukushima H, Nishigaki T, Taniike M, Nishimoto J, Tsukamoto H, Yanagihara I, Ozono K, Okada S. Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe's disease. J Neurochem. 1996 Mar;66(3):1118-24. PMID:8769874
- ↑ Hill CH, Cook GM, Spratley SJ, Fawke S, Graham SC, Deane JE. The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure. Nat Commun. 2018 Jan 11;9(1):151. doi: 10.1038/s41467-017-02361-y. PMID:29323104 doi:http://dx.doi.org/10.1038/s41467-017-02361-y
|
