2wtk

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{{STRUCTURE_2wtk| PDB=2wtk | SCENE= }}
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==STRUCTURE OF THE HETEROTRIMERIC LKB1-STRADALPHA-MO25ALPHA COMPLEX==
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===STRUCTURE OF THE HETEROTRIMERIC LKB1-STRADALPHA-MO25ALPHA COMPLEX===
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<StructureSection load='2wtk' size='340' side='right' caption='[[2wtk]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
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{{ABSTRACT_PUBMED_19892943}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2wtk]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WTK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WTK FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1upl|1upl]], [[1upk|1upk]]</td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wtk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wtk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wtk RCSB], [http://www.ebi.ac.uk/pdbsum/2wtk PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/STK11_HUMAN STK11_HUMAN]] Defects in STK11 are a cause of Peutz-Jeghers syndrome (PJS) [MIM:[http://omim.org/entry/175200 175200]]. PJS is a rare hereditary disease in which there is predisposition to benign and malignant tumors of many organ systems. PJS is an autosomal dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer.<ref>PMID:9425897</ref> <ref>PMID:9760200</ref> <ref>PMID:9428765</ref> <ref>PMID:10408777</ref> <ref>PMID:12372054</ref> <ref>PMID:21411391</ref> Defects in STK11 have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9605748</ref> <ref>PMID:9887330</ref> Note=Defects in STK11 are associated with some sporadic cancers, especially lung cancers. Frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Defects promote lung cancerigenesis process, especially lung cancer progression and metastasis. Confers lung adenocarcinoma the ability to trans-differentiate into squamous cell carcinoma. Also able to promotes lung cancer metastasis, via both cancer-cell autonomous and non-cancer-cell autonomous mechanisms. [[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.
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== Function ==
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[[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/STK11_HUMAN STK11_HUMAN]] Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, leading to promote their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2: it thereby regulates inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neurons polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1 Also acts as a mediator p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways.<ref>PMID:11430832</ref> <ref>PMID:12805220</ref> <ref>PMID:14517248</ref> <ref>PMID:15016379</ref> <ref>PMID:14976552</ref> <ref>PMID:15733851</ref> <ref>PMID:17108107</ref> <ref>PMID:21317932</ref> [[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wt/2wtk_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The LKB1 tumor suppressor is a protein kinase that controls activity of adenine monophosphate-activated protein kinase (AMPK). LKB1 activity is regulated by the pseudokinase STRADalpha and the scaffolding protein MO25alpha, through an unknown, phosphorylation-independent mechanism. We describe the structure of the core heterotrimeric LKB1-STRADalpha-MO25alpha complex, revealing an unusual allosteric mechanism of LKB1 activation. STRADalpha adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRADalpha and MO25alpha promote the active conformation of LKB1, which is stabilised by MO25alpha interacting with the LKB1 activation loop. This previously undescribed mechanism of kinase activation may be relevant to understanding the evolution of other pseudokinases. The structure also reveals how mutations found in Peutz-Jeghers syndrome and other cancers impair LKB1 function.
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==Disease==
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Structure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation.,Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM Science. 2009 Nov 5. PMID:19892943<ref>PMID:19892943</ref>
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[[http://www.uniprot.org/uniprot/STK11_HUMAN STK11_HUMAN]] Defects in STK11 are a cause of Peutz-Jeghers syndrome (PJS) [MIM:[http://omim.org/entry/175200 175200]]. PJS is a rare hereditary disease in which there is predisposition to benign and malignant tumors of many organ systems. PJS is an autosomal dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer.<ref>PMID:9425897</ref><ref>PMID:9760200</ref><ref>PMID:9428765</ref><ref>PMID:10408777</ref><ref>PMID:12372054</ref><ref>PMID:21411391</ref> Defects in STK11 have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9605748</ref><ref>PMID:9887330</ref> Note=Defects in STK11 are associated with some sporadic cancers, especially lung cancers. Frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Defects promote lung cancerigenesis process, especially lung cancer progression and metastasis. Confers lung adenocarcinoma the ability to trans-differentiate into squamous cell carcinoma. Also able to promotes lung cancer metastasis, via both cancer-cell autonomous and non-cancer-cell autonomous mechanisms. [[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.
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[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/STK11_HUMAN STK11_HUMAN]] Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, leading to promote their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2: it thereby regulates inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neurons polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1 Also acts as a mediator p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways.<ref>PMID:11430832</ref><ref>PMID:12805220</ref><ref>PMID:14517248</ref><ref>PMID:15016379</ref><ref>PMID:14976552</ref><ref>PMID:15733851</ref><ref>PMID:17108107</ref><ref>PMID:21317932</ref> [[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>
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</div>
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==About this Structure==
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==See Also==
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[[2wtk]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WTK OCA].
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*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:019892943</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]

Revision as of 02:09, 1 October 2014

STRUCTURE OF THE HETEROTRIMERIC LKB1-STRADALPHA-MO25ALPHA COMPLEX

2wtk, resolution 2.65Å

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