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| | <StructureSection load='5uvg' size='340' side='right'caption='[[5uvg]], [[Resolution|resolution]] 1.85Å' scene=''> | | <StructureSection load='5uvg' size='340' side='right'caption='[[5uvg]], [[Resolution|resolution]] 1.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5uvg]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UVG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UVG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5uvg]] is a 1 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=5UVG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UVG 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></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]] 1.849Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMPD3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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></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=5uvg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uvg OCA], [http://pdbe.org/5uvg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uvg RCSB], [http://www.ebi.ac.uk/pdbsum/5uvg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uvg ProSAT]</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=5uvg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uvg OCA], [https://pdbe.org/5uvg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uvg RCSB], [https://www.ebi.ac.uk/pdbsum/5uvg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uvg ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NSMA2_HUMAN NSMA2_HUMAN]] Catalyzes the hydrolysis of sphingomyelin to form ceramide and phosphocholine. Ceramide mediates numerous cellular functions, such as apoptosis and growth arrest, and is capable of regulating these 2 cellular events independently. Also hydrolyzes sphingosylphosphocholine. Regulates the cell cycle by acting as a growth suppressor in confluent cells. Probably acts as a regulator of postnatal development and participates in bone and dentin mineralization.<ref>PMID:10823942</ref> <ref>PMID:14741383</ref> <ref>PMID:15051724</ref> | + | [https://www.uniprot.org/uniprot/NSMA2_HUMAN NSMA2_HUMAN] Catalyzes the hydrolysis of sphingomyelin to form ceramide and phosphocholine. Ceramide mediates numerous cellular functions, such as apoptosis and growth arrest, and is capable of regulating these 2 cellular events independently. Also hydrolyzes sphingosylphosphocholine. Regulates the cell cycle by acting as a growth suppressor in confluent cells. Probably acts as a regulator of postnatal development and participates in bone and dentin mineralization.<ref>PMID:10823942</ref> <ref>PMID:14741383</ref> <ref>PMID:15051724</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
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| - | Neutral sphingomyelinase 2 (nSMase2, product of the SMPD3 gene) is a key enzyme for ceramide generation that is involved in regulating cellular stress responses and exosome-mediated intercellular communication. nSMase2 is activated by diverse stimuli, including the anionic phospholipid phosphatidylserine. Phosphatidylserine binds to an integral-membrane N-terminal domain (NTD); however, how the NTD activates the C-terminal catalytic domain is unclear. Here, we identify the complete catalytic domain of nSMase2, which was misannotated because of a large insertion. We find the soluble catalytic domain interacts directly with the membrane-associated NTD, which serves as both a membrane anchor and an allosteric activator. The juxtamembrane region, which links the NTD and the catalytic domain, is necessary and sufficient for activation. Furthermore, we provide a mechanistic basis for this phenomenon using the crystal structure of the human nSMase2 catalytic domain determined at 1.85-A resolution. The structure reveals a DNase-I-type fold with a hydrophobic track leading to the active site that is blocked by an evolutionarily conserved motif which we term the "DK switch." Structural analysis of nSMase2 and the extended N-SMase family shows that the DK switch can adopt different conformations to reposition a universally conserved Asp (D) residue involved in catalysis. Mutation of this Asp residue in nSMase2 disrupts catalysis, allosteric activation, stimulation by phosphatidylserine, and pharmacological inhibition by the lipid-competitive inhibitor GW4869. Taken together, these results demonstrate that the DK switch regulates ceramide generation by nSMase2 and is governed by an allosteric interdomain interaction at the membrane interface.
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| - | Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation.,Airola MV, Shanbhogue P, Shamseddine AA, Guja KE, Senkal CE, Maini R, Bartke N, Wu BX, Obeid LM, Garcia-Diaz M, Hannun YA Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):E5549-E5558. doi:, 10.1073/pnas.1705134114. Epub 2017 Jun 26. PMID:28652336<ref>PMID:28652336</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5uvg" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Airola, M V]] | + | [[Category: Airola MV]] |
| - | [[Category: Garcia-Diaz, M]] | + | [[Category: Garcia-Diaz M]] |
| - | [[Category: Guja, K E]] | + | [[Category: Guja KE]] |
| - | [[Category: Hannun, Y A]] | + | [[Category: Hannun YA]] |
| - | [[Category: Hydrolase]]
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| - | [[Category: Sphingomyelinase]]
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