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| - | [[Image:2pme.gif|left|200px]]<br /><applet load="2pme" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2pme, resolution 2.900Å" /> | |
| - | '''The Apo crystal Structure of the glycyl-tRNA synthetase'''<br /> | |
| | | | |
| - | ==Overview== | + | ==The Apo crystal Structure of the glycyl-tRNA synthetase== |
| - | Functional expansion of specific tRNA synthetases in higher organisms is, well documented. These additional functions may explain why dominant, mutations in glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase, cause Charcot-Marie-Tooth (CMT) disease, the most common heritable disease, of the peripheral nervous system. At least 10 disease-causing mutant, alleles of GlyRS have been annotated. These mutations scatter broadly, across the primary sequence and have no apparent unifying connection. Here, we report the structure of wild type and a CMT-causing mutant (G526R) of, homodimeric human GlyRS. The mutation is at the site for synthesis of, glycyl-adenylate, but the rest of the two structures are closely similar., Significantly, the mutant form diffracts to a higher resolution and has a, greater dimer interface. The extra dimer interactions are located, approximately 30 A away from the G526R mutation. Direct experiments, confirm the tighter dimer interaction of the G526R protein. The results, suggest the possible importance of subtle, long-range structural effects, of CMT-causing mutations at the dimer interface. From analysis of a third, crystal, an appended motif, found in higher eukaryote GlyRSs, seems not to, have a role in these long-range effects.
| + | <StructureSection load='2pme' size='340' side='right'caption='[[2pme]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2pme]] 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=2PME OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PME FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</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=2pme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pme OCA], [https://pdbe.org/2pme PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pme RCSB], [https://www.ebi.ac.uk/pdbsum/2pme PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pme ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/GARS_HUMAN GARS_HUMAN] Autosomal dominant Charcot-Marie-Tooth disease type 2D;Distal hereditary motor neuropathy type 5. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/GARS_HUMAN GARS_HUMAN] Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017).<ref>PMID:17544401</ref> <ref>PMID:19710017</ref> <ref>PMID:24898252</ref> <ref>PMID:28675565</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pm/2pme_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2pme ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | ==About this Structure== | + | ==See Also== |
| - | 2PME is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Glycine--tRNA_ligase Glycine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.14 6.1.1.14] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PME OCA].
| + | *[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] |
| - | | + | == References == |
| - | ==Reference== | + | <references/> |
| - | Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation in human glycyl-tRNA synthetase., Xie W, Nangle LA, Zhang W, Schimmel P, Yang XL, Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):9976-81. Epub 2007 Jun 1. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17545306 17545306]
| + | __TOC__ |
| - | [[Category: Glycine--tRNA ligase]]
| + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Xie, W.]] | + | [[Category: Xie W]] |
| - | [[Category: classiia aminoacyl trna synthetase]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:47:57 2008''
| + | |
| Structural highlights
Disease
GARS_HUMAN Autosomal dominant Charcot-Marie-Tooth disease type 2D;Distal hereditary motor neuropathy type 5. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
GARS_HUMAN Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017).[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
References
- ↑ Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK. Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy. FEBS Lett. 2007 Jun 26;581(16):2959-64. Epub 2007 May 29. PMID:17544401 doi:10.1016/j.febslet.2007.05.046
- ↑ Guo RT, Chong YE, Guo M, Yang XL. Crystal structures and biochemical analyses suggest a unique mechanism and role for human glycyl-tRNA synthetase in Ap4A homeostasis. J Biol Chem. 2009 Oct 16;284(42):28968-76. Epub 2009 Aug 26. PMID:19710017 doi:10.1074/jbc.M109.030692
- ↑ Qin X, Hao Z, Tian Q, Zhang Z, Zhou C, Xie W. Cocrystal Structures of Glycyl-tRNA Synthetase in Complex with tRNA Suggest Multiple Conformational States in Glycylation. J Biol Chem. 2014 Jul 18;289(29):20359-69. doi: 10.1074/jbc.M114.557249. Epub, 2014 Jun 4. PMID:24898252 doi:http://dx.doi.org/10.1074/jbc.M114.557249
- ↑ Oprescu SN, Chepa-Lotrea X, Takase R, Golas G, Markello TC, Adams DR, Toro C, Gropman AL, Hou YM, Malicdan MCV, Gahl WA, Tifft CJ, Antonellis A. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Hum Mutat. 2017 Oct;38(10):1412-1420. doi: 10.1002/humu.23287. Epub 2017 Jul 14. PMID:28675565 doi:http://dx.doi.org/10.1002/humu.23287
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