Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling
Cullin 3 (CUL3) is the scaffold of Cullin3 Ring E3-ligases (CRL3s), which use various BTB-adaptor proteins to ubiquitinate numerous substrates targeting their proteasomal degradation. <i>CUL3</i> mutations, responsible for a severe form of familial hyperkalemia and hypertension (FHHt), a...
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MDPI AG
2022-05-01
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| author | Ilektra Kouranti Waed Abdel Khalek Stephani Mazurkiewicz Irmine Loisel-Ferreira Alexis M. Gautreau Lionel Pintard Xavier Jeunemaitre Eric Clauser |
| author_facet | Ilektra Kouranti Waed Abdel Khalek Stephani Mazurkiewicz Irmine Loisel-Ferreira Alexis M. Gautreau Lionel Pintard Xavier Jeunemaitre Eric Clauser |
| author_sort | Ilektra Kouranti |
| collection | DOAJ |
| description | Cullin 3 (CUL3) is the scaffold of Cullin3 Ring E3-ligases (CRL3s), which use various BTB-adaptor proteins to ubiquitinate numerous substrates targeting their proteasomal degradation. <i>CUL3</i> mutations, responsible for a severe form of familial hyperkalemia and hypertension (FHHt), all result in a deletion of exon 9 (amino-acids 403-459) (CUL3-∆9). Surprisingly, while CUL3-∆9 is hyperneddylated, a post-translational modification that typically activates CRL complexes, it is unable to ubiquitinate its substrates. In order to understand the mechanisms behind this loss-of function, we performed comparative label-free quantitative analyses of CUL3 and CUL3-∆9 interactome by mass spectrometry. It was observed that CUL3-∆9 interactions with COP9 and CAND1, both involved in CRL3 complexes’ dynamic assembly, were disrupted. These defects result in a reduction in the dynamic cycling of the CRL3 complexes, making the CRL3-∆9 complex an inactive BTB-adaptor trap, as demonstrated by SILAC experiments. Collectively, the data indicated that the hyperneddylated CUL3-∆9 protein is inactive as a consequence of several structural changes disrupting its dynamic interactions with key regulatory partners. |
| first_indexed | 2024-03-10T04:03:45Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:03:45Z |
| publishDate | 2022-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-df16924b81fd48c9b4988f7b209e66ad2023-11-23T08:27:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-01239515110.3390/ijms23095151Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and CyclingIlektra Kouranti0Waed Abdel Khalek1Stephani Mazurkiewicz2Irmine Loisel-Ferreira3Alexis M. Gautreau4Lionel Pintard5Xavier Jeunemaitre6Eric Clauser7Université Paris Cité, French National Institute of Health and Medical Research (INSERM), Paris Cardiovascular Research Center (PARCC), F-75015 Paris, FranceUniversité Paris Cité, French National Institute of Health and Medical Research (INSERM), Paris Cardiovascular Research Center (PARCC), F-75015 Paris, FranceUniversité Paris Cité, French National Institute of Health and Medical Research (INSERM), Paris Cardiovascular Research Center (PARCC), F-75015 Paris, FranceUniversité Paris Cité, French National Institute of Health and Medical Research (INSERM), Paris Cardiovascular Research Center (PARCC), F-75015 Paris, FranceLaboratory of Structural Biology of the Cell, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, FranceFrench National Centre for Scientific Research (CNRS), Institut Jacques Monod, Université Paris Cité, F-75013 Paris, FranceUniversité Paris Cité, French National Institute of Health and Medical Research (INSERM), Paris Cardiovascular Research Center (PARCC), F-75015 Paris, FranceUniversité Paris Cité, French National Institute of Health and Medical Research (INSERM), Paris Cardiovascular Research Center (PARCC), F-75015 Paris, FranceCullin 3 (CUL3) is the scaffold of Cullin3 Ring E3-ligases (CRL3s), which use various BTB-adaptor proteins to ubiquitinate numerous substrates targeting their proteasomal degradation. <i>CUL3</i> mutations, responsible for a severe form of familial hyperkalemia and hypertension (FHHt), all result in a deletion of exon 9 (amino-acids 403-459) (CUL3-∆9). Surprisingly, while CUL3-∆9 is hyperneddylated, a post-translational modification that typically activates CRL complexes, it is unable to ubiquitinate its substrates. In order to understand the mechanisms behind this loss-of function, we performed comparative label-free quantitative analyses of CUL3 and CUL3-∆9 interactome by mass spectrometry. It was observed that CUL3-∆9 interactions with COP9 and CAND1, both involved in CRL3 complexes’ dynamic assembly, were disrupted. These defects result in a reduction in the dynamic cycling of the CRL3 complexes, making the CRL3-∆9 complex an inactive BTB-adaptor trap, as demonstrated by SILAC experiments. Collectively, the data indicated that the hyperneddylated CUL3-∆9 protein is inactive as a consequence of several structural changes disrupting its dynamic interactions with key regulatory partners.https://www.mdpi.com/1422-0067/23/9/5151WNK kinaseBTB proteinCullinCRL complexinteractome |
| spellingShingle | Ilektra Kouranti Waed Abdel Khalek Stephani Mazurkiewicz Irmine Loisel-Ferreira Alexis M. Gautreau Lionel Pintard Xavier Jeunemaitre Eric Clauser Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling International Journal of Molecular Sciences WNK kinase BTB protein Cullin CRL complex interactome |
| title | Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling |
| title_full | Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling |
| title_fullStr | Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling |
| title_full_unstemmed | Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling |
| title_short | Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling |
| title_sort | cullin 3 exon 9 deletion in familial hyperkalemic hypertension impairs cullin3 ring e3 ligase crl3 dynamic regulation and cycling |
| topic | WNK kinase BTB protein Cullin CRL complex interactome |
| url | https://www.mdpi.com/1422-0067/23/9/5151 |
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