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| | <StructureSection load='6k4r' size='340' side='right'caption='[[6k4r]], [[Resolution|resolution]] 3.11Å' scene=''> | | <StructureSection load='6k4r' size='340' side='right'caption='[[6k4r]], [[Resolution|resolution]] 3.11Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6k4r]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Legph Legph]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6K4R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6K4R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6k4r]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Legionella_pneumophila_subsp._pneumophila_str._Philadelphia_1 Legionella pneumophila subsp. pneumophila str. Philadelphia 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6K4R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6K4R FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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]] 3.109Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lpg2155 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=272624 LEGPH]), CALM1, CALM, CAM, CAM1 ([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=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=6k4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6k4r OCA], [http://pdbe.org/6k4r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6k4r RCSB], [http://www.ebi.ac.uk/pdbsum/6k4r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6k4r 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=6k4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6k4r OCA], [https://pdbe.org/6k4r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6k4r RCSB], [https://www.ebi.ac.uk/pdbsum/6k4r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6k4r ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/CALM1_HUMAN CALM1_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CALM1_HUMAN CALM1_HUMAN]] Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).<ref>PMID:16760425</ref> <ref>PMID:23893133</ref> <ref>PMID:26969752</ref> <ref>PMID:27165696</ref> | + | [https://www.uniprot.org/uniprot/SIDJ_LEGPH SIDJ_LEGPH] Glutamylase that mediates the covalent attachment of glutamate moieties to SdeA on one of the catalytic residues that is required for its mono-ADP-ribosyltransferase activity (PubMed:31330532, PubMed:31330531). In turn, inhibits SdeA ubiquitinating activity. Glutamylates also related SdeB, SdeC and SidE (PubMed:31330531, PubMed:31123136). Glutamylase activity only occurs in the host since it requires host calmodulin (PubMed:28497808, PubMed:31330532, PubMed:31330531, PubMed:31123136). May also reverse the SdeA-mediated substrate ubiquitination by cleaving the phosphodiester bond that links phosphoribosylated ubiquitin to protein substrates via its deubiquitinase activity (PubMed:28497808).<ref>PMID:28497808</ref> <ref>PMID:31123136</ref> <ref>PMID:31330531</ref> <ref>PMID:31330532</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating host cell functions using hundreds of effector proteins delivered via its Dot/Icm secretion system(1). Among these, members of the SidE family (SidEs) regulate multiple cellular processes by a unique phosphoribosyl ubiquitination mechanism that bypasses the canonical ubiquitination machinery(2-4). The activity of SidEs is regulated by SidJ, another Dot/Icm effector(5), but the mechanism of such regulation is not completely understood(6,7). Here we demonstrate that SidJ inhibits the activity of SidEs by inducing covalent attachment of glutamate moieties to E860 of SdeA, which is one of the catalytic residues for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation(2). The inhibition by SidJ is spatially restricted in host cells because its activity requires the eukaryote-specific protein calmodulin (CaM). We solved a structure of SidJ-CaM in complex with adenosine monophosphate (AMP) and found that the ATP utilized is cleaved at the alpha phosphate position by SidJ which in the absence of glutamate or modifiable SdeA undergoes self-AMPylation. Our results reveal an unprecedented mechanism of regulation in bacterial pathogenicity in which a glutamylation reaction that inhibits the activity of virulence factors is activated by host factor-dependent acyl-adenylation.
| + | |
| | | | |
| - | Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase.,Gan N, Zhen X, Liu Y, Xu X, He C, Qiu J, Liu Y, Fujimoto GM, Nakayasu ES, Zhou B, Zhao L, Puvar K, Das C, Ouyang S, Luo ZQ Nature. 2019 Jul 22. pii: 10.1038/s41586-019-1439-1. doi:, 10.1038/s41586-019-1439-1. PMID:31330531<ref>PMID:31330531</ref>
| + | ==See Also== |
| - | | + | *[[Calmodulin 3D structures|Calmodulin 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6k4r" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Legph]] | + | [[Category: Legionella pneumophila subsp. pneumophila str. Philadelphia 1]] |
| - | [[Category: Ouyang, S Y]] | + | [[Category: Ouyang SY]] |
| - | [[Category: A novel kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-cell cycle complex]]
| + | |
| Structural highlights
Function
SIDJ_LEGPH Glutamylase that mediates the covalent attachment of glutamate moieties to SdeA on one of the catalytic residues that is required for its mono-ADP-ribosyltransferase activity (PubMed:31330532, PubMed:31330531). In turn, inhibits SdeA ubiquitinating activity. Glutamylates also related SdeB, SdeC and SidE (PubMed:31330531, PubMed:31123136). Glutamylase activity only occurs in the host since it requires host calmodulin (PubMed:28497808, PubMed:31330532, PubMed:31330531, PubMed:31123136). May also reverse the SdeA-mediated substrate ubiquitination by cleaving the phosphodiester bond that links phosphoribosylated ubiquitin to protein substrates via its deubiquitinase activity (PubMed:28497808).[1] [2] [3] [4]
See Also
References
- ↑ Qiu J, Yu K, Fei X, Liu Y, Nakayasu ES, Piehowski PD, Shaw JB, Puvar K, Das C, Liu X, Luo ZQ. A unique deubiquitinase that deconjugates phosphoribosyl-linked protein ubiquitination. Cell Res. 2017 Jul;27(7):865-881. PMID:28497808 doi:10.1038/cr.2017.66
- ↑ Black MH, Osinski A, Gradowski M, Servage KA, Pawlowski K, Tomchick DR, Tagliabracci VS. Bacterial pseudokinase catalyzes protein polyglutamylation to inhibit the SidE-family ubiquitin ligases. Science. 2019 May 24;364(6442):787-792. doi: 10.1126/science.aaw7446. PMID:31123136 doi:http://dx.doi.org/10.1126/science.aaw7446
- ↑ Gan N, Zhen X, Liu Y, Xu X, He C, Qiu J, Liu Y, Fujimoto GM, Nakayasu ES, Zhou B, Zhao L, Puvar K, Das C, Ouyang S, Luo ZQ. Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase. Nature. 2019 Jul 22. pii: 10.1038/s41586-019-1439-1. doi:, 10.1038/s41586-019-1439-1. PMID:31330531 doi:http://dx.doi.org/10.1038/s41586-019-1439-1
- ↑ Bhogaraju S, Bonn F, Mukherjee R, Adams M, Pfleiderer MM, Galej WP, Matkovic V, Lopez-Mosqueda J, Kalayil S, Shin D, Dikic I. Inhibition of bacterial ubiquitin ligases by SidJ-calmodulin-catalysed glutamylation. Nature. 2019 Jul 22. pii: 10.1038/s41586-019-1440-8. doi:, 10.1038/s41586-019-1440-8. PMID:31330532 doi:http://dx.doi.org/10.1038/s41586-019-1440-8
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