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| | <StructureSection load='5wxn' size='340' side='right'caption='[[5wxn]], [[Resolution|resolution]] 2.93Å' scene=''> | | <StructureSection load='5wxn' size='340' side='right'caption='[[5wxn]], [[Resolution|resolution]] 2.93Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5wxn]] is a 4 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=5WXN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5WXN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5wxn]] is a 4 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=5WXN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WXN FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.93Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">YWHAZ ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></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=5wxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wxn OCA], [http://pdbe.org/5wxn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wxn RCSB], [http://www.ebi.ac.uk/pdbsum/5wxn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wxn 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=5wxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wxn OCA], [https://pdbe.org/5wxn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wxn RCSB], [https://www.ebi.ac.uk/pdbsum/5wxn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wxn ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[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. | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/1433Z_HUMAN 1433Z_HUMAN]] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.<ref>PMID:9360956</ref> <ref>PMID:14578935</ref> <ref>PMID:15071501</ref> <ref>PMID:15644438</ref> <ref>PMID:16376338</ref> [[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> | + | [https://www.uniprot.org/uniprot/1433Z_HUMAN 1433Z_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.<ref>PMID:9360956</ref> <ref>PMID:14578935</ref> <ref>PMID:15071501</ref> <ref>PMID:15644438</ref> <ref>PMID:16376338</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ding, S]] | + | [[Category: Ding S]] |
| - | [[Category: Shi, Z B]] | + | [[Category: Shi ZB]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Protein binding-transferase complex]]
| + | |
| - | [[Category: Protein complex]]
| + | |
| - | [[Category: Tumor suppressor]]
| + | |
| Structural highlights
Function
1433Z_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
The serine/threonine protein kinase liver kinase B1 (LKB1) is a tumour suppressor and plays important roles in development and metabolism. It phosphorylates AMPK and AMPK-related kinases to regulate multiple physiological processes. Mutations in LKB1 often occur in multiple cancers. LKB1 can be suppressed by 14-3-3 proteins in a phosphorylation-dependent manner. Previously, the structure of a 14-3-3zeta-LKB1 fusion protein has been reported, revealing a phosphorylation-independent binding mode of LKB1 to 14-3-3 proteins. Here, the crystal structure of phosphorylated LKB1 peptide in complex with 14-3-3zeta was solved, which provides a structural basis for the phosphorylation-dependent recognition of LKB1 by 14-3-3 proteins.
Structure of the complex of phosphorylated liver kinase B1 and 14-3-3zeta.,Lu Y, Ding S, Zhou R, Wu J Acta Crystallogr F Struct Biol Commun. 2017 Apr 1;73(Pt 4):196-201. doi:, 10.1107/S2053230X17003521. Epub 2017 Mar 22. PMID:28368277[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dubois T, Rommel C, Howell S, Steinhussen U, Soneji Y, Morrice N, Moelling K, Aitken A. 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J Biol Chem. 1997 Nov 14;272(46):28882-8. PMID:9360956
- ↑ Zheng W, Zhang Z, Ganguly S, Weller JL, Klein DC, Cole PA. Cellular stabilization of the melatonin rhythm enzyme induced by nonhydrolyzable phosphonate incorporation. Nat Struct Biol. 2003 Dec;10(12):1054-7. Epub 2003 Oct 26. PMID:14578935 doi:10.1038/nsb1005
- ↑ Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 2004 Apr 21;23(8):1889-99. Epub 2004 Apr 8. PMID:15071501 doi:10.1038/sj.emboj.7600194
- ↑ Ganguly S, Weller JL, Ho A, Chemineau P, Malpaux B, Klein DC. Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1222-7. Epub 2005 Jan 11. PMID:15644438 doi:0406871102
- ↑ Gu YM, Jin YH, Choi JK, Baek KH, Yeo CY, Lee KY. Protein kinase A phosphorylates and regulates dimerization of 14-3-3 epsilon. FEBS Lett. 2006 Jan 9;580(1):305-10. Epub 2005 Dec 19. PMID:16376338 doi:S0014-5793(05)01485-7
- ↑ Lu Y, Ding S, Zhou R, Wu J. Structure of the complex of phosphorylated liver kinase B1 and 14-3-3zeta. Acta Crystallogr F Struct Biol Commun. 2017 Apr 1;73(Pt 4):196-201. doi:, 10.1107/S2053230X17003521. Epub 2017 Mar 22. PMID:28368277 doi:http://dx.doi.org/10.1107/S2053230X17003521
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