6whb: Difference between revisions
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==MEKK1 TOG domain (548-867)== | ==MEKK1 TOG domain (548-867)== | ||
<StructureSection load='6whb' size='340' side='right'caption='[[6whb]]' scene=''> | <StructureSection load='6whb' size='340' side='right'caption='[[6whb]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WHB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WHB FirstGlance]. <br> | <table><tr><td colspan='2'>[[6whb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WHB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WHB FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6whb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6whb OCA], [http://pdbe.org/6whb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6whb RCSB], [http://www.ebi.ac.uk/pdbsum/6whb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6whb ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6whb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6whb OCA], [http://pdbe.org/6whb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6whb RCSB], [http://www.ebi.ac.uk/pdbsum/6whb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6whb ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[http://www.uniprot.org/uniprot/M3K1_HUMAN M3K1_HUMAN]] 46,XY partial gonadal dysgenesis;46,XY complete gonadal dysgenesis. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/M3K1_HUMAN M3K1_HUMAN]] Component of a protein kinase signal transduction cascade (PubMed:9808624). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:9808624). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:9808624).<ref>PMID:17761173</ref> <ref>PMID:9808624</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The MEKK1 protein is a pivotal kinase activator of responses to cellular stress. Activation of MEKK1 can trigger various responses, including mitogen-activated protein (MAP) kinases, NF-kappaB signaling, or cell migration. Notably, MEKK1 activity is triggered by microtubule-targeting chemotherapies, among other stressors. Here we show that MEKK1 contains a previously unidentified tumor overexpressed gene (TOG) domain. The MEKK1 TOG domain binds to tubulin heterodimers-a canonical function of TOG domains-but is unusual in that it appears alone rather than as part of a multi-TOG array, and has structural features distinct from previously characterized TOG domains. MEKK1 TOG demonstrates a clear preference for binding curved tubulin heterodimers, which exist in soluble tubulin and at sites of microtubule polymerization and depolymerization. Mutations disrupting tubulin binding decrease microtubule density at the leading edge of polarized cells, suggesting that tubulin binding may play a role in MEKK1 activity at the cellular periphery. We also show that MEKK1 mutations at the tubulin-binding interface of the TOG domain recur in patient-derived tumor sequences, suggesting selective enrichment of tumor cells with disrupted MEKK1-microtubule association. Together, these findings provide a direct link between the MEKK1 protein and tubulin, which is likely to be relevant to cancer cell migration and response to microtubule-modulating therapies. | |||
A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers.,Filipcik P, Latham SL, Cadell AL, Day CL, Croucher DR, Mace PD Proc Natl Acad Sci U S A. 2020 Aug 17. pii: 2006429117. doi:, 10.1073/pnas.2006429117. PMID:32817551<ref>PMID:32817551</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6whb" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Filipcik P]] | [[Category: Mitogen-activated protein kinase kinase kinase]] | ||
[[Category: Mace | [[Category: Filipcik, P]] | ||
[[Category: Mace, P D]] | |||
[[Category: Localization]] | |||
[[Category: Protein-binding]] | |||
[[Category: Signaling protein]] | |||
[[Category: Tubulin-binding]] | |||
Revision as of 10:09, 2 September 2020
MEKK1 TOG domain (548-867)MEKK1 TOG domain (548-867)
Structural highlights
Disease[M3K1_HUMAN] 46,XY partial gonadal dysgenesis;46,XY complete gonadal dysgenesis. The disease is caused by mutations affecting the gene represented in this entry. Function[M3K1_HUMAN] Component of a protein kinase signal transduction cascade (PubMed:9808624). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:9808624). May phosphorylate the MAPK8/JNK1 kinase (PubMed:17761173). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:9808624).[1] [2] Publication Abstract from PubMedThe MEKK1 protein is a pivotal kinase activator of responses to cellular stress. Activation of MEKK1 can trigger various responses, including mitogen-activated protein (MAP) kinases, NF-kappaB signaling, or cell migration. Notably, MEKK1 activity is triggered by microtubule-targeting chemotherapies, among other stressors. Here we show that MEKK1 contains a previously unidentified tumor overexpressed gene (TOG) domain. The MEKK1 TOG domain binds to tubulin heterodimers-a canonical function of TOG domains-but is unusual in that it appears alone rather than as part of a multi-TOG array, and has structural features distinct from previously characterized TOG domains. MEKK1 TOG demonstrates a clear preference for binding curved tubulin heterodimers, which exist in soluble tubulin and at sites of microtubule polymerization and depolymerization. Mutations disrupting tubulin binding decrease microtubule density at the leading edge of polarized cells, suggesting that tubulin binding may play a role in MEKK1 activity at the cellular periphery. We also show that MEKK1 mutations at the tubulin-binding interface of the TOG domain recur in patient-derived tumor sequences, suggesting selective enrichment of tumor cells with disrupted MEKK1-microtubule association. Together, these findings provide a direct link between the MEKK1 protein and tubulin, which is likely to be relevant to cancer cell migration and response to microtubule-modulating therapies. A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers.,Filipcik P, Latham SL, Cadell AL, Day CL, Croucher DR, Mace PD Proc Natl Acad Sci U S A. 2020 Aug 17. pii: 2006429117. doi:, 10.1073/pnas.2006429117. PMID:32817551[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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