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3ade

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Revision as of 16:23, 22 December 2021

Crystal Structure of Keap1 in Complex with Sequestosome-1/p62

Structural highlights

3ade is a 2 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:	Inrf2, Keap1, 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] [SQSTM_MOUSE] Required both for the formation and autophagic degradation of polyubiquitin-containing bodies, called ALIS (aggresome-like induced structures). Links ALIS to the autophagic machinery via direct interaction with MAP1 LC3 family members. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Adapter that mediates the interaction between TRAF6 and CYLD.^[3] ^[4]

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

Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.,Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M Nat Cell Biol. 2010 Mar;12(3):213-23. Epub 2010 Feb 21. PMID:20173742^[5]

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
↑ Duran A, Serrano M, Leitges M, Flores JM, Picard S, Brown JP, Moscat J, Diaz-Meco MT. The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell. 2004 Feb;6(2):303-9. PMID:14960283
↑ Jin W, Chang M, Paul EM, Babu G, Lee AJ, Reiley W, Wright A, Zhang M, You J, Sun SC. Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest. 2008 May;118(5):1858-66. doi: 10.1172/JCI34257. PMID:18382763 doi:10.1172/JCI34257
↑ Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010 Mar;12(3):213-23. Epub 2010 Feb 21. PMID:20173742 doi:10.1038/ncb2021

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Keap1 in Complex with Sequestosome-1/p62==
-<StructureSection load='3ade' size='340' side='right' caption='[[3ade]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='3ade' size='340' side='right'caption='[[3ade]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ade]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ADE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ADE FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ade]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ADE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ADE FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Inrf2, Keap1, Kiaa0132 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Inrf2, Keap1, Kiaa0132 ([https://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=3ade FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ade OCA], [http://pdbe.org/3ade PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ade RCSB], [http://www.ebi.ac.uk/pdbsum/3ade PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ade 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=3ade FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ade OCA], [https://pdbe.org/3ade PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ade RCSB], [https://www.ebi.ac.uk/pdbsum/3ade PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ade ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/KEAP1_MOUSE 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).<ref>PMID:9887101</ref> <ref>PMID:12682069</ref>  [[http://www.uniprot.org/uniprot/SQSTM_MOUSE SQSTM_MOUSE]] Required both for the formation and autophagic degradation of polyubiquitin-containing bodies, called ALIS (aggresome-like induced structures). Links ALIS to the autophagic machinery via direct interaction with MAP1 LC3 family members. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Adapter that mediates the interaction between TRAF6 and CYLD.<ref>PMID:14960283</ref> <ref>PMID:18382763</ref>
+[[https://www.uniprot.org/uniprot/KEAP1_MOUSE 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).<ref>PMID:9887101</ref> <ref>PMID:12682069</ref>  [[https://www.uniprot.org/uniprot/SQSTM_MOUSE SQSTM_MOUSE]] Required both for the formation and autophagic degradation of polyubiquitin-containing bodies, called ALIS (aggresome-like induced structures). Links ALIS to the autophagic machinery via direct interaction with MAP1 LC3 family members. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Adapter that mediates the interaction between TRAF6 and CYLD.<ref>PMID:14960283</ref> <ref>PMID:18382763</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 31: / Line 31: @@
 ==See Also==
-*[[Kelch-like protein|Kelch-like protein]]
+*[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]]
-*[[Sequestosome|Sequestosome]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Lk3 transgenic mice]]
 [[Category: Kurokawa, H]]

3ade

From Proteopedia

Revision as of 16:23, 22 December 2021

Crystal Structure of Keap1 in Complex with Sequestosome-1/p62

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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