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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2006-3-1
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pubmed:databankReference |
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pubmed:abstractText |
Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction. To elucidate the molecular mechanism of the Keap1 and Nrf2 interaction, we resolved the six-bladed beta propeller crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed that extensive inter- and intrablade hydrogen bonds maintain the structural integrity and proper association of Keap1 with Nrf2. A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues. We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2. These results provide a structural basis for the loss of Keap1 function and gain of Nrf2 function.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Cytoskeletal Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Glycosylases,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-(Apurinic or Apyrimidinic...,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/KEAP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Keap1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/NEIL2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/NF-E2-Related Factor 2,
http://linkedlifedata.com/resource/pubmed/chemical/NFE2L2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1097-2765
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
3
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pubmed:volume |
21
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
689-700
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:16507366-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:16507366-Amino Acid Sequence,
pubmed-meshheading:16507366-Animals,
pubmed-meshheading:16507366-Binding Sites,
pubmed-meshheading:16507366-Crystallography, X-Ray,
pubmed-meshheading:16507366-Cytoskeletal Proteins,
pubmed-meshheading:16507366-DNA Glycosylases,
pubmed-meshheading:16507366-DNA-(Apurinic or Apyrimidinic Site) Lyase,
pubmed-meshheading:16507366-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:16507366-Humans,
pubmed-meshheading:16507366-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:16507366-Lung Neoplasms,
pubmed-meshheading:16507366-Mice,
pubmed-meshheading:16507366-Molecular Sequence Data,
pubmed-meshheading:16507366-NF-E2-Related Factor 2,
pubmed-meshheading:16507366-Peptide Fragments,
pubmed-meshheading:16507366-Point Mutation,
pubmed-meshheading:16507366-Protein Structure, Tertiary,
pubmed-meshheading:16507366-Proteins,
pubmed-meshheading:16507366-Structure-Activity Relationship
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pubmed:year |
2006
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pubmed:articleTitle |
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer.
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pubmed:affiliation |
RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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