ArticleThe Journal of biological chemistry2016
Structural Studies of the Nedd4 WW Domains and Their Selectivity for the Connexin43 (Cx43) Carboxyl Terminus.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
- Nedd4L-mediated stabilization of morphogenetic protein receptor 2 in lung fibroblasts confers protection against pulmonary fibrosis.Signal transduction and targeted therapy · 2026Article
- Pharmacological Inhibition of Small Extracellular Vesicle Secretion by ALK5i SD-208 via Lysosomal Rerouting of CD63+ Compartments.Journal of extracellular vesicles · 2026Article
- The relationship between Connexin 43 (Cx43) and partner protein, human discs large homologue-1 (Dlg1) during wound closure in keratinocytes.Cell and tissue research · 2026Article
- Cochlear endoplasmic reticulum stress causes connexin 26 degradation is involved in age-related hearing loss.iScience · 2025Article
- Cx45 regulation by kinases and impact of expression in heart failure.Journal of molecular and cellular cardiology · 2025Article
- NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases.Biomolecules · 2024Review
- The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation.Cellular and molecular life sciences : CMLS · 2024Article
- Endocytosis and Endocytic Motifs across the Connexin Gene Family.International journal of molecular sciences · 2023Article
- The intercalated disc: a unique organelle for electromechanical synchrony in cardiomyocytes.Physiological reviews · 2023Review
- Regulation of Cx43 Gap Junction Intercellular Communication by Bruton's Tyrosine Kinase and Interleukin-2-Inducible T-Cell Kinase.Biomolecules · 2023Article
- The roles of connexins and gap junctions in the progression of cancer.Cell communication and signaling : CCS · 2023Review
- Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer.International journal of molecular sciences · 2022Review
- Review
- Orchestrating serine/threonine phosphorylation and elucidating downstream effects by short linear motifs.The Biochemical journal · 2022Review
- Molecular Interactions between Two LMP2A PY Motifs of EBV and WW Domains of E3 Ubiquitin Ligase AIP4.Life (Basel, Switzerland) · 2021Article
- Control of ribosomal protein synthesis by the Microprocessor complex.Science signaling · 2021Article
- Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin Ligase Subfamily in p53 Signaling and the DNA Damage Response.Frontiers in oncology · 2021Review
- Src Regulation of Cx43 Phosphorylation and Gap Junction Turnover.Biomolecules · 2020Article
- Article
- Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system.FASEB bioAdvances · 2020Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Neuronal precursor cell-expressed developmentally down-regulated 4 (Nedd4) was the first ubiquitin protein ligase identified to interact with connexin43 (Cx43), and its suppressed expression results in accumulation of gap junction plaques at the plasma membrane. Nedd4-mediated ubiquitination of Cx43 is required to recruit Eps15 and target Cx43 to the endocytic pathway. Although the Cx43 residues that undergo ubiquitination are still unknown, in this study we address other unresolved questions pertaining to the molecular mechanisms mediating the direct interaction between Nedd4 (WW1-3 domains) and Cx43 (carboxyl terminus (CT)). All three WW domains display a similar three antiparallel β-strand structure and interact with the same Cx43CT(283)PPXY(286)sequence. Although Tyr(286)is essential for the interaction, MAPK phosphorylation of the preceding serine residues (Ser(P)(279)and Ser(P)(282)) increases the binding affinity by 2-fold for the WW domains (WW2 > WW3 ≫ WW1). The structure of the WW2·Cx43CT(276-289)(Ser(P)(279), Ser(P)(282)) complex reveals that coordination of Ser(P)(282)with the end of β-strand 3 enables Ser(P)(279)to interact with the back face of β-strand 3 (Tyr(286)is on the front face) and loop 2, forming a horseshoe-shaped arrangement. The close sequence identity of WW2 with WW1 and WW3 residues that interact with the Cx43CT PPXY motif and Ser(P)(279)/Ser(P)(282)strongly suggests that the significantly lower binding affinity of WW1 is the result of a more rigid structure. This study presents the first structure illustrating how phosphorylation of the Cx43CT domain helps mediate the interaction with a molecular partner involved in gap junction regulation.
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