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3wn7

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Revision as of 13:28, 19 April 2017

Crystal Structure of Keap1 in Complex with the N-terminal region of the Nrf2 transcription factor

Structural highlights

3wn7 is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	Keap1, Inrf2, Kiaa0132 (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KEAP1_MOUSE] Retains NFE2L2/NRF2 in the cytosol. Functions as substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. May also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome (By similarity).^[1] ^[2] [NF2L2_MOUSE] Transcription activator that binds to antioxidant response (ARE) elements in the promoter regions of target genes. Important for the coordinated up-regulation of genes in response to oxidative stress. May be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region.^[3]

Publication Abstract from PubMed

Transcription factor Nrf2 (NF-E2-related factor 2) coordinately regulates cytoprotective gene expression, but under unstressed conditions, Nrf2 is degraded rapidly through Keap1 (Kelch-like ECH-associated protein 1)-mediated ubiquitination. Nrf2 harbors two Keap1-binding motifs, DLG and ETGE. Interactions between these two motifs and Keap1 constitute a key regulatory nexus for cellular Nrf2 activity through the formation of a two-site binding hinge-and-latch mechanism. In this study, we determined the minimum Keap1-binding sequence of the DLG motif, the low-affinity latch site, and defined a new DLGex motif that covers a sequence much longer than that previously defined. We have successfully clarified the crystal structure of the Keap1-DC-DLGex complex at 1.6 A. DLGex possesses a complicated helix structure, which interprets well the human-cancer-derived loss-of-function mutations in DLGex. In thermodynamic analyses, Keap1-DLGex binding is characterized as enthalpy and entropy driven, while Keap1-ETGE binding is characterized as purely enthalpy driven. In kinetic analyses, Keap1-DLGex binding follows a fast-association and fast-dissociation model, while Keap1-ETGE binding contains a slow-reaction step that leads to a stable conformation. These results demonstrate that the mode of DLGex binding to Keap1 is distinct from that of ETGE structurally, thermodynamically, and kinetically and support our contention that the DLGex motif serves as a converter transmitting environmental stress to Nrf2 induction as the latch site.

Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1.,Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M Mol Cell Biol. 2014 Mar;34(5):832-46. doi: 10.1128/MCB.01191-13. Epub 2013 Dec, 23. PMID:24366543^[4]

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

References

↑ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999 Jan 1;13(1):76-86. PMID:9887101
↑ McMahon M, Itoh K, Yamamoto M, Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003 Jun 13;278(24):21592-600. Epub 2003 Apr 7. PMID:12682069 doi:10.1074/jbc.M300931200
↑ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999 Jan 1;13(1):76-86. PMID:9887101
↑ Fukutomi T, Takagi K, Mizushima T, Ohuchi N, Yamamoto M. Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol. 2014 Mar;34(5):832-46. doi: 10.1128/MCB.01191-13. Epub 2013 Dec, 23. PMID:24366543 doi:http://dx.doi.org/10.1128/MCB.01191-13

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3wn7"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Keap1 in Complex with the N-terminal region of the Nrf2 transcription factor==
 <StructureSection load='3wn7' size='340' side='right' caption='[[3wn7]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Keap1, Inrf2, Kiaa0132 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=3wn7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wn7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wn7 RCSB], [http://www.ebi.ac.uk/pdbsum/3wn7 PDBsum]</span></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=3wn7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wn7 OCA], [http://pdbe.org/3wn7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wn7 RCSB], [http://www.ebi.ac.uk/pdbsum/3wn7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wn7 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3wn7" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Kelch-like ECH-associated protein 1|Kelch-like ECH-associated protein 1]]
+*[[Kelch-like protein|Kelch-like protein]]
 == References ==
 <references/>

3wn7

From Proteopedia

Revision as of 13:28, 19 April 2017

Crystal Structure of Keap1 in Complex with the N-terminal region of the Nrf2 transcription factor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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