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| | ==Structure of a product bound phosphatase== | | ==Structure of a product bound phosphatase== |
| - | <StructureSection load='4rkk' size='340' side='right' caption='[[4rkk]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='4rkk' size='340' side='right'caption='[[4rkk]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4rkk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RKK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RKK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4rkk]] is a 2 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=4RKK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RKK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.4Å</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=4rkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rkk OCA], [http://pdbe.org/4rkk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rkk RCSB], [http://www.ebi.ac.uk/pdbsum/4rkk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rkk ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=PRD_900009:alpha-maltotriose'>PRD_900009</scene>, <scene name='pdbligand=PRD_900010:alpha-maltotetraose'>PRD_900010</scene>, <scene name='pdbligand=PRD_900035:alpha-maltohexaose'>PRD_900035</scene></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=4rkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rkk OCA], [https://pdbe.org/4rkk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rkk RCSB], [https://www.ebi.ac.uk/pdbsum/4rkk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rkk ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/EPM2A_HUMAN EPM2A_HUMAN]] Lafora disease. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/EPM2A_HUMAN EPM2A_HUMAN] Lafora disease. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/EPM2A_HUMAN EPM2A_HUMAN]] Has both dual-specificity protein phosphatase and glucan phosphatase activities. Together with the E3 ubiquitin ligase NHLRC1/malin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. Dephosphorylates phosphotyrosine, phosphoserine and phosphothreonine substrates in vitro. Has also been shown to dephosphorylate MAPT. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway. Isoform 2, an inactive phosphatase, could function as a dominant-negative regulator for the phosphatase activity of isoform 1.<ref>PMID:11001928</ref> <ref>PMID:11220751</ref> <ref>PMID:16901901</ref> <ref>PMID:18070875</ref> <ref>PMID:18617530</ref> <ref>PMID:19036738</ref> <ref>PMID:20453062</ref> <ref>PMID:23624058</ref> | + | [https://www.uniprot.org/uniprot/EPM2A_HUMAN EPM2A_HUMAN] Has both dual-specificity protein phosphatase and glucan phosphatase activities. Together with the E3 ubiquitin ligase NHLRC1/malin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. Dephosphorylates phosphotyrosine, phosphoserine and phosphothreonine substrates in vitro. Has also been shown to dephosphorylate MAPT. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway. Isoform 2, an inactive phosphatase, could function as a dominant-negative regulator for the phosphatase activity of isoform 1.<ref>PMID:11001928</ref> <ref>PMID:11220751</ref> <ref>PMID:16901901</ref> <ref>PMID:18070875</ref> <ref>PMID:18617530</ref> <ref>PMID:19036738</ref> <ref>PMID:20453062</ref> <ref>PMID:23624058</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.
| + | |
| - | | + | |
| - | Structural Mechanism of Laforin Function in Glycogen Dephosphorylation and Lafora Disease.,Raththagala M, Brewer MK, Parker MW, Sherwood AR, Wong BK, Hsu S, Bridges TM, Paasch BC, Hellman LM, Husodo S, Meekins DA, Taylor AO, Turner BD, Auger KD, Dukhande VV, Chakravarthy S, Sanz P, Woods VL Jr, Li S, Vander Kooi CW, Gentry MS Mol Cell. 2014 Dec 23. pii: S1097-2765(14)00915-0. doi:, 10.1016/j.molcel.2014.11.020. PMID:25544560<ref>PMID:25544560</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4rkk" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Kooi, C W.Vander]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Carbohydrate binding module]] | + | [[Category: Large Structures]] |
| - | [[Category: Dual specificity phosphatase]] | + | [[Category: Vander Kooi CW]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Phosphatase]]
| + | |
| Structural highlights
4rkk is a 2 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 2.4Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
EPM2A_HUMAN Lafora disease. The disease is caused by mutations affecting the gene represented in this entry.
Function
EPM2A_HUMAN Has both dual-specificity protein phosphatase and glucan phosphatase activities. Together with the E3 ubiquitin ligase NHLRC1/malin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. Dephosphorylates phosphotyrosine, phosphoserine and phosphothreonine substrates in vitro. Has also been shown to dephosphorylate MAPT. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway. Isoform 2, an inactive phosphatase, could function as a dominant-negative regulator for the phosphatase activity of isoform 1.[1] [2] [3] [4] [5] [6] [7] [8]
References
- ↑ Ganesh S, Agarwala KL, Ueda K, Akagi T, Shoda K, Usui T, Hashikawa T, Osada H, Delgado-Escueta AV, Yamakawa K. Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Hum Mol Genet. 2000 Sep 22;9(15):2251-61. PMID:11001928
- ↑ Minassian BA, Andrade DM, Ianzano L, Young EJ, Chan E, Ackerley CA, Scherer SW. Laforin is a cell membrane and endoplasmic reticulum-associated protein tyrosine phosphatase. Ann Neurol. 2001 Feb;49(2):271-5. PMID:11220751
- ↑ Worby CA, Gentry MS, Dixon JE. Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. 2006 Oct 13;281(41):30412-8. Epub 2006 Aug 10. PMID:16901901 doi:http://dx.doi.org/10.1074/jbc.M606117200
- ↑ Worby CA, Gentry MS, Dixon JE. Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. 2008 Feb 15;283(7):4069-76. Epub 2007 Dec 10. PMID:18070875 doi:http://dx.doi.org/10.1074/jbc.M708712200
- ↑ Dubey D, Ganesh S. Modulation of functional properties of laforin phosphatase by alternative splicing reveals a novel mechanism for the EPM2A gene in Lafora progressive myoclonus epilepsy. Hum Mol Genet. 2008 Oct 1;17(19):3010-20. doi: 10.1093/hmg/ddn199. Epub 2008 Jul , 10. PMID:18617530 doi:http://dx.doi.org/10.1093/hmg/ddn199
- ↑ Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, Parihar R, Ganesh S. The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet. 2009 Feb 15;18(4):688-700. doi: 10.1093/hmg/ddn398. Epub 2008 Nov , 25. PMID:19036738 doi:http://dx.doi.org/10.1093/hmg/ddn398
- ↑ Aguado C, Sarkar S, Korolchuk VI, Criado O, Vernia S, Boya P, Sanz P, de Cordoba SR, Knecht E, Rubinsztein DC. Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum Mol Genet. 2010 Jul 15;19(14):2867-76. doi: 10.1093/hmg/ddq190. Epub 2010 May, 7. PMID:20453062 doi:http://dx.doi.org/10.1093/hmg/ddq190
- ↑ Rubio-Villena C, Garcia-Gimeno MA, Sanz P. Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex. Int J Biochem Cell Biol. 2013 Jul;45(7):1479-88. doi:, 10.1016/j.biocel.2013.04.019. Epub 2013 Apr 26. PMID:23624058 doi:http://dx.doi.org/10.1016/j.biocel.2013.04.019
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