Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling - Archive ouverte HAL Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2022

Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling

(1, 2) , (1, 2) , (1, 2) , (1, 2) , (3, 4) , (5) , (1, 2) , (1, 2)
1
2
3
4
5

Abstract

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. CUL3 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.
Fichier principal
Vignette du fichier
ijms-23-05151-v3.pdf (5.9 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

inserm-03671394 , version 1 (18-05-2022)

Identifiers

Cite

Ilektra Kouranti, Waed Abdel Khalek, Stephani Mazurkiewicz, Irmine Loisel-Ferreira, Alexis Gautreau, et al.. Cullin 3 Exon 9 Deletion in Familial Hyperkalemic Hypertension Impairs Cullin3-Ring-E3 Ligase (CRL3) Dynamic Regulation and Cycling. International Journal of Molecular Sciences, 2022, 23 (9), pp.5151. ⟨10.3390/ijms23095151⟩. ⟨inserm-03671394⟩
23 View
15 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More