6qhd

From Proteopedia

(Difference between revisions)

Current revision

Lysine acetylated and tyrosine phosphorylated STAT3 in a complex with DNA

Structural highlights

6qhd is a 4 chain structure with sequence from Homo sapiens and Murine adenovirus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.85Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

STAT3_HUMAN Chronic lymphoproliferative disorder of natural killer cells;Autosomal dominant hyper-IgE syndrome;STAT3-related early-onset multisystem autoimmune disease;T-cell large granular lymphocyte leukemia;Permanent neonatal diabetes mellitus. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

STAT3_HUMAN Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:17344214, PubMed:18242580, PubMed:23084476). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity).[UniProtKB:P42227]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

The signal transducer and activator of transcription 3 (STAT3) protein is activated by phosphorylation of a specific tyrosine residue (Tyr705) in response to various extracellular signals. STAT3 activity was also found to be regulated by acetylation of Lys685. However, the molecular mechanism by which Lys685 acetylation affects the transcriptional activity of STAT3 remains elusive. By genetically encoding the co-translational incorporation of acetyl-lysine into position Lys685 and co-expression of STAT3 with the Elk receptor tyrosine kinase, we were able to characterize site-specifically acetylated, and simultaneously acetylated and phosphorylated STAT3. We measured the effect of acetylation on the crystal structure, and DNA binding affinity and specificity of Tyr705-phosphorylated and non-phosphorylated STAT3. In addition, we monitored the deacetylation of acetylated Lys685 by reconstituting the mammalian enzymatic deacetylation reaction in live bacteria. Surprisingly, we found that acetylation, per se, had no effect on the crystal structure, and DNA binding affinity or specificity of STAT3, implying that the previously observed acetylation-dependent transcriptional activity of STAT3 involves an additional cellular component. In addition, we discovered that Tyr705-phosphorylation protects Lys685 from deacetylation in bacteria, providing a new possible explanation for the observed correlation between STAT3 activity and Lys685 acetylation.

Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine.,Belo Y, Mielko Z, Nudelman H, Afek A, Ben-David O, Shahar A, Zarivach R, Gordan R, Arbely E Biochim Biophys Acta Gen Subj. 2019 Jun 3;1863(9):1343-1350. doi:, 10.1016/j.bbagen.2019.05.019. PMID:31170499^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tsai YT, Su YH, Fang SS, Huang TN, Qiu Y, Jou YS, Shih HM, Kung HJ, Chen RH. Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation. Mol Cell Biol. 2000 Mar;20(6):2043-54. PMID:10688651
↑ Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N, Matsuda T. The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun. 2002 Oct 4;297(4):811-7. doi:, 10.1016/s0006-291x(02)02291-x. PMID:12359225 doi:http://dx.doi.org/10.1016/s0006-291x(02)02291-x
↑ Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003 Jul 15;63(14):3923-30. PMID:12873986
↑ Dreuw A, Radtke S, Pflanz S, Lippok BE, Heinrich PC, Hermanns HM. Characterization of the signaling capacities of the novel gp130-like cytokine receptor. J Biol Chem. 2004 Aug 20;279(34):36112-20. Epub 2004 Jun 11. PMID:15194700 doi:http://dx.doi.org/10.1074/jbc.M401122200
↑ Saxena NK, Vertino PM, Anania FA, Sharma D. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem. 2007 May 4;282(18):13316-25. doi: 10.1074/jbc.M609798200. Epub 2007 , Mar 7. PMID:17344214 doi:http://dx.doi.org/10.1074/jbc.M609798200
↑ Jiang H, Yu J, Guo H, Song H, Chen S. Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun. 2008 Mar 28;368(1):1-5. doi:, 10.1016/j.bbrc.2007.04.004. Epub 2007 Sep 14. PMID:18242580 doi:http://dx.doi.org/10.1016/j.bbrc.2007.04.004
↑ Shen S, Niso-Santano M, Adjemian S, Takehara T, Malik SA, Minoux H, Souquere S, Marino G, Lachkar S, Senovilla L, Galluzzi L, Kepp O, Pierron G, Maiuri MC, Hikita H, Kroemer R, Kroemer G. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol Cell. 2012 Dec 14;48(5):667-80. doi: 10.1016/j.molcel.2012.09.013. Epub 2012 , Oct 17. PMID:23084476 doi:http://dx.doi.org/10.1016/j.molcel.2012.09.013
↑ Ma L, Huang C, Wang XJ, Xin DE, Wang LS, Zou QC, Zhang YS, Tan MD, Wang YM, Zhao TC, Chatterjee D, Altura RA, Wang C, Xu YS, Yang JH, Fan YS, Han BH, Si J, Zhang X, Cheng J, Chang Z, Chin YE. Lysyl Oxidase 3 Is a Dual-Specificity Enzyme Involved in STAT3 Deacetylation and Deacetylimination Modulation. Mol Cell. 2017 Jan 19;65(2):296-309. doi: 10.1016/j.molcel.2016.12.002. Epub 2017, Jan 5. PMID:28065600 doi:http://dx.doi.org/10.1016/j.molcel.2016.12.002
↑ Belo Y, Mielko Z, Nudelman H, Afek A, Ben-David O, Shahar A, Zarivach R, Gordan R, Arbely E. Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine. Biochim Biophys Acta Gen Subj. 2019 Jun 3;1863(9):1343-1350. doi:, 10.1016/j.bbagen.2019.05.019. PMID:31170499 doi:http://dx.doi.org/10.1016/j.bbagen.2019.05.019

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6qhd"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6qhd is ON HOLD  until Paper Publication
+==Lysine acetylated and tyrosine phosphorylated STAT3 in a complex with DNA==
+<StructureSection load='6qhd' size='340' side='right'caption='[[6qhd]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6qhd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Murine_adenovirus_1 Murine adenovirus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QHD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QHD FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></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=6qhd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qhd OCA], [https://pdbe.org/6qhd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qhd RCSB], [https://www.ebi.ac.uk/pdbsum/6qhd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qhd ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/STAT3_HUMAN STAT3_HUMAN] Chronic lymphoproliferative disorder of natural killer cells;Autosomal dominant hyper-IgE syndrome;STAT3-related early-onset multisystem autoimmune disease;T-cell large granular lymphocyte leukemia;Permanent neonatal diabetes mellitus. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/STAT3_HUMAN STAT3_HUMAN] Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors (PubMed:10688651, PubMed:12359225, PubMed:12873986, PubMed:15194700, PubMed:17344214, PubMed:18242580, PubMed:23084476). Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene (PubMed:17344214). May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:12873986). Binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes (PubMed:12359225). Activated by IL31 through IL31RA (PubMed:15194700). Acts as a regulator of inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): deacetylation and oxidation of lysine residues by LOXL3, leads to disrupt STAT3 dimerization and inhibit its transcription activity (PubMed:28065600). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (PubMed:17344214). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation (By similarity). May play an apoptotic role by transctivating BIRC5 expression under LEP activation (PubMed:18242580). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (PubMed:23084476). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion (By similarity).[UniProtKB:P42227]<ref>PMID:10688651</ref> <ref>PMID:12359225</ref> <ref>PMID:12873986</ref> <ref>PMID:15194700</ref> <ref>PMID:17344214</ref> <ref>PMID:18242580</ref> <ref>PMID:23084476</ref> <ref>PMID:28065600</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The signal transducer and activator of transcription 3 (STAT3) protein is activated by phosphorylation of a specific tyrosine residue (Tyr705) in response to various extracellular signals. STAT3 activity was also found to be regulated by acetylation of Lys685. However, the molecular mechanism by which Lys685 acetylation affects the transcriptional activity of STAT3 remains elusive. By genetically encoding the co-translational incorporation of acetyl-lysine into position Lys685 and co-expression of STAT3 with the Elk receptor tyrosine kinase, we were able to characterize site-specifically acetylated, and simultaneously acetylated and phosphorylated STAT3. We measured the effect of acetylation on the crystal structure, and DNA binding affinity and specificity of Tyr705-phosphorylated and non-phosphorylated STAT3. In addition, we monitored the deacetylation of acetylated Lys685 by reconstituting the mammalian enzymatic deacetylation reaction in live bacteria. Surprisingly, we found that acetylation, per se, had no effect on the crystal structure, and DNA binding affinity or specificity of STAT3, implying that the previously observed acetylation-dependent transcriptional activity of STAT3 involves an additional cellular component. In addition, we discovered that Tyr705-phosphorylation protects Lys685 from deacetylation in bacteria, providing a new possible explanation for the observed correlation between STAT3 activity and Lys685 acetylation.
-Authors:
+Unexpected implications of STAT3 acetylation revealed by genetic encoding of acetyl-lysine.,Belo Y, Mielko Z, Nudelman H, Afek A, Ben-David O, Shahar A, Zarivach R, Gordan R, Arbely E Biochim Biophys Acta Gen Subj. 2019 Jun 3;1863(9):1343-1350. doi:, 10.1016/j.bbagen.2019.05.019. PMID:31170499<ref>PMID:31170499</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6qhd" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Murine adenovirus 1]]
+[[Category: Arbely E]]
+[[Category: Belo Y]]
+[[Category: Shahar A]]
+[[Category: Zarivach R]]

6qhd

From Proteopedia

Current revision

Lysine acetylated and tyrosine phosphorylated STAT3 in a complex with DNA

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox