Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family
Keap1 (Kelch-like ECH-associated protein 1) is one of the major negative regulators of the transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2), which induces the expression of numerous proteins defending the cell against different stress conditions. Keap1 is generally negatively...
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MDPI AG
2023-04-01
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| Series: | Life |
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| Online Access: | https://www.mdpi.com/2075-1729/13/4/1045 |
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| author | Gregory A. Shilovsky Daria V. Dibrova |
| author_facet | Gregory A. Shilovsky Daria V. Dibrova |
| author_sort | Gregory A. Shilovsky |
| collection | DOAJ |
| description | Keap1 (Kelch-like ECH-associated protein 1) is one of the major negative regulators of the transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2), which induces the expression of numerous proteins defending the cell against different stress conditions. Keap1 is generally negatively regulated by post-translational modification (mostly via its cysteine residues) and interaction with other proteins that compete with Nrf2 for binding. Cysteine residues in Keap1 have different effects on protein regulation, as basic residues (Lys, Arg, and His) in close proximity to them increase cysteine modification potential. In this paper, we present an evolutionary analysis of residues involved in both mechanisms of Keap1 regulation in the broader context of the KLHL protein family in vertebrates. We identified the typical domain structure of the KLHL protein family in several proteins outside of this family (namely in KBTBD proteins 2, 3, 4, 6, 7, 8, 12 and 14). We found several cysteines that are flanked by basic residues (namely, C14, C38, C151, C226, C241, C273, C288, C297, C319, and C613) and, therefore, may be considered more susceptible to regulatory modification. The Nrf2 binding site is completely conserved in Keap1 in vertebrates but is absent or located in nonaligned DA and BC loops of the Kelch domain within the KLHL family. The development of specific substrate binding regions could be an evolutionary factor of diversification in the KLHL protein family. |
| first_indexed | 2024-03-11T04:49:48Z |
| format | Article |
| id | doaj.art-2dee8ff6f33e4c2e86f5f21097e90d2e |
| institution | Directory Open Access Journal |
| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-11T04:49:48Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Life |
| spelling | doaj.art-2dee8ff6f33e4c2e86f5f21097e90d2e2023-11-17T20:07:24ZengMDPI AGLife2075-17292023-04-01134104510.3390/life13041045Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL FamilyGregory A. Shilovsky0Daria V. Dibrova1Faculty of Biology, Lomonosov Moscow State University, 119192 Moscow, RussiaBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, RussiaKeap1 (Kelch-like ECH-associated protein 1) is one of the major negative regulators of the transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2), which induces the expression of numerous proteins defending the cell against different stress conditions. Keap1 is generally negatively regulated by post-translational modification (mostly via its cysteine residues) and interaction with other proteins that compete with Nrf2 for binding. Cysteine residues in Keap1 have different effects on protein regulation, as basic residues (Lys, Arg, and His) in close proximity to them increase cysteine modification potential. In this paper, we present an evolutionary analysis of residues involved in both mechanisms of Keap1 regulation in the broader context of the KLHL protein family in vertebrates. We identified the typical domain structure of the KLHL protein family in several proteins outside of this family (namely in KBTBD proteins 2, 3, 4, 6, 7, 8, 12 and 14). We found several cysteines that are flanked by basic residues (namely, C14, C38, C151, C226, C241, C273, C288, C297, C319, and C613) and, therefore, may be considered more susceptible to regulatory modification. The Nrf2 binding site is completely conserved in Keap1 in vertebrates but is absent or located in nonaligned DA and BC loops of the Kelch domain within the KLHL family. The development of specific substrate binding regions could be an evolutionary factor of diversification in the KLHL protein family.https://www.mdpi.com/2075-1729/13/4/1045evolutionNrf2Keap1KLHL proteinsKelch domainslongevity |
| spellingShingle | Gregory A. Shilovsky Daria V. Dibrova Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family Life evolution Nrf2 Keap1 KLHL proteins Kelch domains longevity |
| title | Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family |
| title_full | Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family |
| title_fullStr | Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family |
| title_full_unstemmed | Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family |
| title_short | Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family |
| title_sort | regulation of cell proliferation and nrf2 mediated antioxidant defense conservation of keap1 cysteines and nrf2 binding site in the context of the evolution of klhl family |
| topic | evolution Nrf2 Keap1 KLHL proteins Kelch domains longevity |
| url | https://www.mdpi.com/2075-1729/13/4/1045 |
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