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| | ==Structure of STRAD and MO25== | | ==Structure of STRAD and MO25== |
| - | <StructureSection load='3gni' size='340' side='right' caption='[[3gni]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='3gni' size='340' side='right'caption='[[3gni]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3gni]] is a 2 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=3GNI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3GNI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3gni]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GNI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GNI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1upk|1upk]], [[1upl|1upl]]</td></tr> | + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1upk|1upk]], [[1upl|1upl]]</div></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CAB39, MO25, CGI-66 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), STRADA, LYK5, STRAD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CAB39, MO25, CGI-66 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), STRADA, LYK5, STRAD ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3gni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gni OCA], [http://pdbe.org/3gni PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3gni RCSB], [http://www.ebi.ac.uk/pdbsum/3gni PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3gni 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=3gni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gni OCA], [https://pdbe.org/3gni PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gni RCSB], [https://www.ebi.ac.uk/pdbsum/3gni PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gni ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/STRAA_HUMAN STRAA_HUMAN]] Note=A homozygous 7-kb deletion involving STRADA is a cause of a syndrome characterized by polyhydramnios, megalencephaly and symptomatic epilepsy. | + | [[https://www.uniprot.org/uniprot/STRAA_HUMAN STRAA_HUMAN]] Note=A homozygous 7-kb deletion involving STRADA is a cause of a syndrome characterized by polyhydramnios, megalencephaly and symptomatic epilepsy. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CAB39_HUMAN CAB39_HUMAN]] Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1. [[http://www.uniprot.org/uniprot/STRAA_HUMAN STRAA_HUMAN]] Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1. Adopts a closed conformation typical of active protein kinases and binds STK11/LKB1 as a pseudosubstrate, promoting conformational change of STK11/LKB1 in an active conformation.<ref>PMID:12805220</ref> <ref>PMID:14517248</ref> <ref>PMID:19892943</ref> | + | [[https://www.uniprot.org/uniprot/CAB39_HUMAN CAB39_HUMAN]] Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1. [[https://www.uniprot.org/uniprot/STRAA_HUMAN STRAA_HUMAN]] Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1. Adopts a closed conformation typical of active protein kinases and binds STK11/LKB1 as a pseudosubstrate, promoting conformational change of STK11/LKB1 in an active conformation.<ref>PMID:12805220</ref> <ref>PMID:14517248</ref> <ref>PMID:19892943</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Aalten, D M.F van]] | | [[Category: Aalten, D M.F van]] |
| | [[Category: Alessi, D R]] | | [[Category: Alessi, D R]] |
| Structural highlights
3gni is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | |
| Gene: | CAB39, MO25, CGI-66 (HUMAN), STRADA, LYK5, STRAD (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[STRAA_HUMAN] Note=A homozygous 7-kb deletion involving STRADA is a cause of a syndrome characterized by polyhydramnios, megalencephaly and symptomatic epilepsy.
Function
[CAB39_HUMAN] Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1. [STRAA_HUMAN] Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1. Adopts a closed conformation typical of active protein kinases and binds STK11/LKB1 as a pseudosubstrate, promoting conformational change of STK11/LKB1 in an active conformation.[1] [2] [3]
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
Pseudokinases lack essential residues for kinase activity, yet are emerging as important regulators of signal transduction networks. The pseudokinase STRAD activates the LKB1 tumour suppressor by forming a heterotrimeric complex with LKB1 and the scaffolding protein MO25. Here, we describe the structure of STRADalpha in complex with MO25alpha. The structure reveals an intricate web of interactions between STRADalpha and MO25alpha involving the alphaC-helix of STRADalpha, reminiscent of the mechanism by which CDK2 interacts with cyclin A. Surprisingly, STRADalpha binds ATP and displays a closed conformation and an ordered activation loop, typical of active protein kinases. Inactivity is accounted for by nonconservative substitution of almost all essential catalytic residues. We demonstrate that binding of ATP enhances the affinity of STRADalpha for MO25alpha, and conversely, binding of MO25alpha promotes interaction of STRADalpha with ATP. Mutagenesis studies reveal that association of STRADalpha with either ATP or MO25alpha is essential for LKB1 activation. We conclude that ATP and MO25alpha cooperate to maintain STRADalpha in an "active" closed conformation required for LKB1 activation. It has recently been demonstrated that a mutation in human STRADalpha that truncates a C-terminal region of the pseudokinase domain leads to the polyhydramnios, megalencephaly, symptomatic epilepsy (PMSE) syndrome. We demonstrate this mutation destabilizes STRADalpha and prevents association with LKB1. In summary, our findings describe one of the first structures of a genuinely inactive pseudokinase. The ability of STRADalpha to activate LKB1 is dependent on a closed "active" conformation, aided by ATP and MO25alpha binding. Thus, the function of STRADalpha is mediated through an active kinase conformation rather than kinase activity. It is possible that other pseudokinases exert their function through nucleotide binding and active conformations.
ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor.,Zeqiraj E, Filippi BM, Goldie S, Navratilova I, Boudeau J, Deak M, Alessi DR, van Aalten DM PLoS Biol. 2009 Jun 9;7(6):e1000126. Epub 2009 Jun 9. PMID:19513107[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 2003 Jun 16;22(12):3062-72. PMID:12805220 doi:10.1093/emboj/cdg292
- ↑ Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A, Schutkowski M, Prescott AR, Clevers HC, Alessi DR. MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 2003 Oct 1;22(19):5102-14. PMID:14517248 doi:10.1093/emboj/cdg490
- ↑ Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM. Structure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation. Science. 2009 Nov 5. PMID:19892943
- ↑ Zeqiraj E, Filippi BM, Goldie S, Navratilova I, Boudeau J, Deak M, Alessi DR, van Aalten DM. ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor. PLoS Biol. 2009 Jun 9;7(6):e1000126. Epub 2009 Jun 9. PMID:19513107 doi:10.1371/journal.pbio.1000126
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