ArticleMolecular biology of the cell2012
Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function.
Article in Molecular biology of the cell, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Association between the p.V37I variant of GJB2 and hearing loss: a pedigree and meta-analysis.Oncotarget · 2017Pooled it
- Probenecid-Mediated Pannexin-1 Inhibition Preserves βFGF-Driven Regenerative Responses in Human Dermal Fibroblasts.International journal of molecular sciences · 2026Article
- Connexin 26 in Hearing Health and Disease: StructuralFoundations, Mutation Mechanisms, and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Deficient Gap Junction Coupling in Two Common Hearing Loss-Related Variants of GJB2.Clinical and experimental otorhinolaryngology · 2024Article
- Differential Regulation of Hemichannels and Gap Junction Channels by RhoA GTPase and Actin Cytoskeleton: A Comparative Analysis of Cx43 and Cx26.International journal of molecular sciences · 2024Article
- Calcium Regulation of Connexin Hemichannels.International journal of molecular sciences · 2024Review
- Connexin channels and hemichannels are modulated differently by charge reversal at residues forming the intracellular pocket.Biological research · 2024Article
- Cx31.1 can selectively intermix with co-expressed connexins to facilitate its assembly into gap junctions.Journal of cell science · 2024Article
- Functional Consequences of Pathogenic Variants of theBiomolecules · 2023Review
- Cytomembrane Trafficking Pathways of Connexin 26, 30, and 43.International journal of molecular sciences · 2023Review
- Molecular Mechanisms and Clinical Phenotypes ofBiology · 2023Review
- Simulation-predicted and -explained inheritance model of pathogenicity confirmed by transgenic mice models.Computational and structural biotechnology journal · 2023Article
- Expression of KID syndromic mutation Cx26S17F produces hyperactive hemichannels in supporting cells of the organ of Corti.Frontiers in cell and developmental biology · 2022Article
- Polydisperse molecular architecture of connexin 26/30 heteromeric hemichannels revealed by atomic force microscopy imaging.The Journal of biological chemistry · 2020Article
- Article
- Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease.Frontiers in genetics · 2019Article
- Concatenation of Human Connexin26 (hCx26) and Human Connexin46 (hCx46) for the Analysis of Heteromeric Gap Junction Hemichannels and Heterotypic Gap Junction Channels.International journal of molecular sciences · 2018Article
- Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome.Scientific reports · 2018Article
- Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease.International journal of molecular sciences · 2018Review
- Newborn genetic screening for hearing impairment: a population-based longitudinal study.Genetics in medicine : official journal of the American College of Medical Genetics · 2017Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
To identify motifs involved in oligomerization of the gap junction protein Cx26, we studied individual transmembrane (TM) domains and the full-length protein. Using the TOXCAT assay for interactions of isolated TM α-helices, we found that TM1, a Cx26 pore domain, had a strong propensity to homodimerize. We identified amino acids Val-37-Ala-40 (VVAA) as the TM1 motif required for homodimerization. Two deafness-associated Cx26 mutations localized in this region, Cx26V37I and Cx26A40G, differentially affected dimerization. TM1-V37I dimerized only weakly, whereas TM1-A40G did not dimerize. When the full-length mutants were expressed in HeLa cells, both Cx26V37I and Cx26A40G formed oligomers less efficiently than wild-type Cx26. A Cx26 cysteine substitution mutant, Cx26V37C formed dithiothreitol-sensitive dimers. Substitution mutants of Val-37 formed intercellular channels with reduced function, while mutants of Ala-40 did not form functional gap junction channels. Unlike wild-type Cx26, neither Cx26V37I nor Cx26A40G formed functional hemichannels in low extracellular calcium. Thus the VVAA motif of Cx26 is critical for TM1 dimerization, hexamer formation, and channel function. The differential effects of VVAA mutants on hemichannels and gap junction channels imply that inter-TM interactions can differ in unapposed and docked hemichannels. Moreover, Cx26 oligomerization appears dependent on transient TM1 dimerization as an intermediate step.
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