Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains
Keap1 is a substrate adaptor of a Cullin 3-based E3 ubiquitin ligase complex that recognizes Nrf2, and also acts as a cellular sensor for xenobiotics and oxidative stresses. Nrf2 is a transcriptional factor regulating the expression of cytoprotective enzyme genes in response to such stresses. Under...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-02, Vol.107 (7), p.2842-2847 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Ogura, Toshihiko Tong, Kit I Mio, Kazuhiro Maruyama, Yuusuke Kurokawa, Hirofumi Sato, Chikara Yamamoto, Masayuki |
| description | Keap1 is a substrate adaptor of a Cullin 3-based E3 ubiquitin ligase complex that recognizes Nrf2, and also acts as a cellular sensor for xenobiotics and oxidative stresses. Nrf2 is a transcriptional factor regulating the expression of cytoprotective enzyme genes in response to such stresses. Under unstressed conditions Keap1 binds Nrf2 and results in rapid degradation of Nrf2 through the proteasome pathway. In contrast, upon exposure to oxidative and electrophilic stress, reactive cysteine residues in intervening region (IVR) and Broad complex, Tramtrack, and Bric-à-Brac domains of Keap1 are modified by electrophiles. This modification prevents Nrf2 from rapid degradation and induces Nrf2 activity by repression of Keap1. Here we report the structure of mouse Keap1 homodimer by single particle electron microscopy. Three-dimensional reconstruction at 24-Å resolution revealed two large spheres attached by short linker arms to the sides of a small forked-stem structure, resembling a cherry-bob. Each sphere has a tunnel corresponding to the central hole of the β-propeller domain, as determined by x-ray crystallography. The IVR domain appears to surround the core of the β-propeller domain. The unexpected proximity of IVR to the β-propeller domain suggests that any distortions generated during modification of reactive cysteine residues in the IVR domain may send a derepression signal to the β-propeller domain and thereby stabilize Nrf2. This study thus provides a structural basis for the two-site binding and hinge-latch model of stress sensing by the Nrf2-Keap1 system. |
| doi_str_mv | 10.1073/pnas.0914036107 |
| format | Article |
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Nrf2 is a transcriptional factor regulating the expression of cytoprotective enzyme genes in response to such stresses. Under unstressed conditions Keap1 binds Nrf2 and results in rapid degradation of Nrf2 through the proteasome pathway. In contrast, upon exposure to oxidative and electrophilic stress, reactive cysteine residues in intervening region (IVR) and Broad complex, Tramtrack, and Bric-à-Brac domains of Keap1 are modified by electrophiles. This modification prevents Nrf2 from rapid degradation and induces Nrf2 activity by repression of Keap1. Here we report the structure of mouse Keap1 homodimer by single particle electron microscopy. Three-dimensional reconstruction at 24-Å resolution revealed two large spheres attached by short linker arms to the sides of a small forked-stem structure, resembling a cherry-bob. Each sphere has a tunnel corresponding to the central hole of the β-propeller domain, as determined by x-ray crystallography. The IVR domain appears to surround the core of the β-propeller domain. The unexpected proximity of IVR to the β-propeller domain suggests that any distortions generated during modification of reactive cysteine residues in the IVR domain may send a derepression signal to the β-propeller domain and thereby stabilize Nrf2. This study thus provides a structural basis for the two-site binding and hinge-latch model of stress sensing by the Nrf2-Keap1 system.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0914036107</identifier><identifier>PMID: 20133743</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adaptor Proteins, Signal Transducing - chemistry ; Adaptor Proteins, Signal Transducing - metabolism ; Amino acids ; Animals ; Antibodies ; Binding sites ; Biological Sciences ; Crystal structure ; Crystallography, X-Ray ; Cytoskeletal Proteins - chemistry ; Cytoskeletal Proteins - metabolism ; Cytoskeletal Proteins - ultrastructure ; Density ; Dimerization ; Dimers ; Enzymes ; Gene expression ; Image analysis ; Kelch-Like ECH-Associated Protein 1 ; Mice ; Microscopy, Electron, Transmission ; Models, Molecular ; Molecular structure ; Molecules ; NF-E2-Related Factor 2 - metabolism ; Oxidative stress ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary - genetics ; Protein Structure, Tertiary - physiology ; Proteins ; Tunnels</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-02, Vol.107 (7), p.2842-2847</ispartof><rights>Copyright National Academy of Sciences Feb 16, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-fa89407b7ab3b03e26254508bef0db3c11b25961c697d52eff1f567f3689fd673</citedby><cites>FETCH-LOGICAL-c488t-fa89407b7ab3b03e26254508bef0db3c11b25961c697d52eff1f567f3689fd673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/7.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40536779$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40536779$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20133743$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ogura, Toshihiko</creatorcontrib><creatorcontrib>Tong, Kit I</creatorcontrib><creatorcontrib>Mio, Kazuhiro</creatorcontrib><creatorcontrib>Maruyama, Yuusuke</creatorcontrib><creatorcontrib>Kurokawa, Hirofumi</creatorcontrib><creatorcontrib>Sato, Chikara</creatorcontrib><creatorcontrib>Yamamoto, Masayuki</creatorcontrib><title>Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Keap1 is a substrate adaptor of a Cullin 3-based E3 ubiquitin ligase complex that recognizes Nrf2, and also acts as a cellular sensor for xenobiotics and oxidative stresses. 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The IVR domain appears to surround the core of the β-propeller domain. The unexpected proximity of IVR to the β-propeller domain suggests that any distortions generated during modification of reactive cysteine residues in the IVR domain may send a derepression signal to the β-propeller domain and thereby stabilize Nrf2. 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Nrf2 is a transcriptional factor regulating the expression of cytoprotective enzyme genes in response to such stresses. Under unstressed conditions Keap1 binds Nrf2 and results in rapid degradation of Nrf2 through the proteasome pathway. In contrast, upon exposure to oxidative and electrophilic stress, reactive cysteine residues in intervening region (IVR) and Broad complex, Tramtrack, and Bric-à-Brac domains of Keap1 are modified by electrophiles. This modification prevents Nrf2 from rapid degradation and induces Nrf2 activity by repression of Keap1. Here we report the structure of mouse Keap1 homodimer by single particle electron microscopy. Three-dimensional reconstruction at 24-Å resolution revealed two large spheres attached by short linker arms to the sides of a small forked-stem structure, resembling a cherry-bob. Each sphere has a tunnel corresponding to the central hole of the β-propeller domain, as determined by x-ray crystallography. The IVR domain appears to surround the core of the β-propeller domain. The unexpected proximity of IVR to the β-propeller domain suggests that any distortions generated during modification of reactive cysteine residues in the IVR domain may send a derepression signal to the β-propeller domain and thereby stabilize Nrf2. This study thus provides a structural basis for the two-site binding and hinge-latch model of stress sensing by the Nrf2-Keap1 system.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>20133743</pmid><doi>10.1073/pnas.0914036107</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - chemistry Adaptor Proteins, Signal Transducing - metabolism Amino acids Animals Antibodies Binding sites Biological Sciences Crystal structure Crystallography, X-Ray Cytoskeletal Proteins - chemistry Cytoskeletal Proteins - metabolism Cytoskeletal Proteins - ultrastructure Density Dimerization Dimers Enzymes Gene expression Image analysis Kelch-Like ECH-Associated Protein 1 Mice Microscopy, Electron, Transmission Models, Molecular Molecular structure Molecules NF-E2-Related Factor 2 - metabolism Oxidative stress Protein Binding Protein Conformation Protein Structure, Tertiary - genetics Protein Structure, Tertiary - physiology Proteins Tunnels |
| title | Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains |
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