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| | ==Solution structure of the T22G mutant of N-terminal SH3 domain of DRK (DRKN SH3 DOMAIN)== | | ==Solution structure of the T22G mutant of N-terminal SH3 domain of DRK (DRKN SH3 DOMAIN)== |
| - | <StructureSection load='2a37' size='340' side='right' caption='[[2a37]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''> | + | <StructureSection load='2a37' size='340' side='right'caption='[[2a37]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2a37]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Drome Drome]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A37 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2A37 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2a37]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A37 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A37 FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2a36|2a36]], [[1q37|1q37]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">drk, E(sev)2B, CG6033 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7227 DROME])</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=2a37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a37 OCA], [https://pdbe.org/2a37 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a37 RCSB], [https://www.ebi.ac.uk/pdbsum/2a37 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a37 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=2a37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a37 OCA], [http://pdbe.org/2a37 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2a37 RCSB], [http://www.ebi.ac.uk/pdbsum/2a37 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DRK_DROME DRK_DROME]] Required for proper signaling by sevenless. May act to stimulate the ability of Sos to catalyze Ras1 activation by linking sevenless and Sos in a signaling complex.<ref>PMID:8462097</ref> <ref>PMID:8462098</ref> | + | [https://www.uniprot.org/uniprot/GRAP_DROME GRAP_DROME] Adapter protein which modulates signaling mediated by several receptor tyrosine kinases such as sev and Ack (PubMed:8462097, PubMed:22615583, PubMed:8462098). Required for proper signaling by sevenless (PubMed:8462097, PubMed:8462098). May act to stimulate the ability of Sos to catalyze Ras1 activation by linking sevenless and Sos in a signaling complex (PubMed:8462097, PubMed:8462098). Required for functional and morphological integrities of the scolopidia, sensory neurons and the antennal mechanosensory and motor center (AMMC) brain neuropil (PubMed:30610177). Required for Ack-dependent suppression of apoptosis in the eye (PubMed:22615583).<ref>PMID:22615583</ref> <ref>PMID:30610177</ref> <ref>PMID:8462097</ref> <ref>PMID:8462098</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a3/2a37_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a3/2a37_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Drome]] | |
| - | [[Category: Bezsonova, I]] | |
| - | [[Category: Choy, W Y]] | |
| - | [[Category: Forman-Kay, J D]] | |
| - | [[Category: Singer, A]] | |
| - | [[Category: Tollinger, M]] | |
| - | [[Category: Drk]] | |
| | [[Category: Drosophila melanogaster]] | | [[Category: Drosophila melanogaster]] |
| - | [[Category: Sh3 fragment]] | + | [[Category: Large Structures]] |
| - | [[Category: Signaling protein]] | + | [[Category: Bezsonova I]] |
| | + | [[Category: Choy W-Y]] |
| | + | [[Category: Forman-Kay JD]] |
| | + | [[Category: Singer A]] |
| | + | [[Category: Tollinger M]] |
| Structural highlights
Function
GRAP_DROME Adapter protein which modulates signaling mediated by several receptor tyrosine kinases such as sev and Ack (PubMed:8462097, PubMed:22615583, PubMed:8462098). Required for proper signaling by sevenless (PubMed:8462097, PubMed:8462098). May act to stimulate the ability of Sos to catalyze Ras1 activation by linking sevenless and Sos in a signaling complex (PubMed:8462097, PubMed:8462098). Required for functional and morphological integrities of the scolopidia, sensory neurons and the antennal mechanosensory and motor center (AMMC) brain neuropil (PubMed:30610177). Required for Ack-dependent suppression of apoptosis in the eye (PubMed:22615583).[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.
Publication Abstract from PubMed
The N-terminal SH3 domain of the Drosophila adapter protein Drk (drkN SH3 domain) is marginally stable (DeltaG(U) = 1 kcal/mol) and exists in equilibrium between folded and highly populated unfolded states. The single substitution T22G, however, completely stabilizes the protein (DeltaG(U) = 4.0 kcal/mol). To probe the causes of instability of the wild-type (WT) protein and the dramatic stabilization of the mutant, we determined and compared nuclear magnetic resonance structures of the folded WT and mutant drkN SH3 domains. Residual dipolar coupling (RDC) and carbonyl chemical-shift anisotropy (C'-CSA) restraints measured for the WT and T22G domains were used for calculating the structures. The structures for the WT and mutant are highly similar. Thr22 of the WT and Gly22 of the mutant are at the i + 2 position of the diverging, type-II beta-turn. Interestingly, not only Gly22 but also Thr22 successfully adopt an alpha(L) conformation, required at this position of the turn, despite the fact that positive phi values are energetically unfavorable and normally disallowed for threonine residues. Forcing the Thr22 residue into this unnatural conformation increases the free energy of the folded state of the WT domain relative to its T22G mutant. Evidence for residual helix formation in the diverging turn region has been previously reported for the unfolded state of the WT drkN SH3 domain, and this, in addition to other residual structure, has been proposed to play a role in decreasing the free energy of the unfolded state of the protein. Together these data provide evidence that both increasing the free energy of the folded state and decreasing the free energy of the unfolded state of the protein contribute to instability of the WT drkN SH3 domain.
Structural comparison of the unstable drkN SH3 domain and a stable mutant.,Bezsonova I, Singer A, Choy WY, Tollinger M, Forman-Kay JD Biochemistry. 2005 Nov 29;44(47):15550-60. PMID:16300404[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schoenherr JA, Drennan JM, Martinez JS, Chikka MR, Hall MC, Chang HC, Clemens JC. Drosophila activated Cdc42 kinase has an anti-apoptotic function. PLoS Genet. 2012;8(5):e1002725. doi: 10.1371/journal.pgen.1002725. Epub 2012 May , 17. PMID:22615583 doi:http://dx.doi.org/10.1371/journal.pgen.1002725
- ↑ Li C, Bademci G, Subasioglu A, Diaz-Horta O, Zhu Y, Liu J, Mitchell TG, Abad C, Seyhan S, Duman D, Cengiz FB, Tokgoz-Yilmaz S, Blanton SH, Farooq A, Walz K, Zhai RG, Tekin M. Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1347-1352. doi:, 10.1073/pnas.1810951116. Epub 2019 Jan 4. PMID:30610177 doi:http://dx.doi.org/10.1073/pnas.1810951116
- ↑ Simon MA, Dodson GS, Rubin GM. An SH3-SH2-SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro. Cell. 1993 Apr 9;73(1):169-77. PMID:8462097
- ↑ Olivier JP, Raabe T, Henkemeyer M, Dickson B, Mbamalu G, Margolis B, Schlessinger J, Hafen E, Pawson T. A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell. 1993 Apr 9;73(1):179-91. PMID:8462098
- ↑ Bezsonova I, Singer A, Choy WY, Tollinger M, Forman-Kay JD. Structural comparison of the unstable drkN SH3 domain and a stable mutant. Biochemistry. 2005 Nov 29;44(47):15550-60. PMID:16300404 doi:10.1021/bi0512795
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