Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function

Jara, Oscar; Acuña, Rodrigo; García, Isaac E.; Maripillán, Jaime; Figueroa, Vania; Sáez, Juan C.; Araya-Secchi, Raúl; Lagos, Carlos F.; Pérez-Acle, Tomás; Berthoud, Viviana M.; Beyer, Eric C.; Martı́nez, Agustı́n D.

doi:10.1091/mbc.e11-12-1058

Cited by 41 publications

(68 citation statements)

References 42 publications

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“…21,27 However, biochemical and electrophysiological studies of cell lines showed that p.V37I reduced the oligomerization efficiency of Cx26, the protein encoded by GJB2, and significantly compromised the channel function of gap junctions. 28 Consistent with the experiments in cell lines, several clinical studies supported that homozygosity for p.V37I is associated with mild to moderate SNHI in humans. 23,[29][30][31][32] Analyses based on serial audiometric data in children with bi-allelic GJB2 mutations further revealed that, among a wide variety of different GJB2 mutations, progression of SNHI was particularly common among carriers of p.V37I either in homozygosity or in compound heterozygosity with another GJB2 mutation.…”

Section: Discussionsupporting

confidence: 69%

Newborn genetic screening for hearing impairment: a population-based longitudinal study

Tsai

Hung

et al. 2017

Genetics in Medicine

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Section: Discussionsupporting

confidence: 69%

Newborn genetic screening for hearing impairment: a population-based longitudinal study

Tsai

Hung

et al. 2017

Genetics in Medicine

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“…Maeda et al (124) speculate that the extracellular half of TM2 and TM4 and the extracellular loops are likely to form the protein/protein interfaces that allow Cx subunits to oligomerize into hexameric connexons (homo-/heteromeric interactions), since these regions contain most of the interaction sites of Cx subunits. However, using TOXCAT assays to study the interaction of isolated transmembrane ␣-helices, Jara et al (76) very recently identified a critical role of the first transmembrane domain of Cx26, and specifically of residues V 37 VAA 40 , in regulating Cx-dimerization, hexamer formation, and channel function. The extracellular loops (E1, E2) of two connected hemichannels (homo-/heterotypic interactions) form concentric, antiparallel ␤-barrels, which make a tight seal in the extracellular space between the opposing PMs (48, 147,199) (FIGURE 2, B AND C).…”

Section: The 3d Structure Of a Gj Channel Provides Functional Cues Rementioning

confidence: 99%

Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation

et al. 2013

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Gap junctions (GJs) are the only known cellular structures that allow a direct cell-to-cell transfer of signaling molecules by forming densely packed arrays or "plaques" of hydrophilic channels that bridge the apposing membranes of neighboring cells. The crucial role of GJ-mediated intercellular communication (GJIC) for all aspects of multicellular life, including coordination of development, tissue function, and cell homeostasis, has been well documented. Assembly and degradation of these membrane channels is a complex process that includes biosynthesis of the connexin (Cx) subunit proteins (innexins in invertebrates) on endoplasmic reticulum (ER) membranes, oligomerization of compatible subunits into hexameric hemichannels (connexons), delivery of the connexons to the plasma membrane (PM), head-on docking of compatible connexons in the extracellular space at distinct locations, arrangement of channels into dynamic spatially and temporally organized GJ channel plaques, as well as internalization of GJs into the cytoplasm followed by their degradation. Clearly, precise modulation of GJIC, biosynthesis, and degradation are crucial for accurate function, and much research currently addresses how these fundamental processes are regulated. Here, we review posttranslational protein modifications (e.g., phosphorylation and ubiquitination) and the binding of protein partners (e.g., the scaffolding protein ZO-1) known to regulate GJ biosynthesis, internalization, and degradation. We also look closely at the atomic resolution structure of a GJ channel, since the structure harbors vital cues relevant to GJ biosynthesis and turnover.

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“…According to the crystal structure of Cx26, the first transmembrane domain is the major pore-lining helix that is involved in prominent intraconnexin interactions with all other transmembrane domains to stabilize the basic structure of the connexin subunit (Maeda et al, 2009). In addition, the V37 amino acid is located in a motif, 37 VVAA 40 , that is conserved between Cx26 and Cx30 (Maeda et al, 2009;Smith et al, 2002), and, as demonstrated by the V37I Cx26 mutant, mutations within this particular motif reduce hexamer formation and channel function (Jara et al, 2012). Importantly, the V37E Cx30 mutation involves a unique and crucial substitution of a glutamic acid residue for a hydrophobic valine, which we propose alters crucial intraconnexin interactions and Cx30 stability, resulting in improper folding and protein accumulation in the ER.…”

Section: The Loss-of-function V37e Mutant Linked To Clouston and Kidmentioning

confidence: 99%

Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies

Berger

Kelly

Lajoie

et al. 2014

Journal of Cell Science

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Connexin 30 (Cx30), a member of the large gap junction protein family, plays a role in the homeostasis of the epidermis and inner ear through gap junctional intercellular communication (GJIC). Here, we investigated the underlying mechanisms of four autosomal dominant Cx30 gene mutations linked to hearing loss and/or various skin diseases. First, the T5M mutant linked to non-syndromic hearing loss formed functional gap junction channels and hemichannels, similar to wild type Cx30. The loss-of-function V37E mutant associated with Clouston syndrome or keratitis-ichthyosis-deafness syndrome was retained in the endoplasmic reticulum and significantly induced apoptosis. The G59R mutant linked to Vohwinkel and Bart-Pumphrey syndromes was retained primarily in the Golgi apparatus and exhibited loss of gap junction channel and hemichannel function, but did not cause cell death. Lastly, the A88V mutant related to Clouston syndrome also significantly induced apoptosis, although through an endoplasmic reticulum-independent mechanism. Collectively, we discovered that four unique Cx30 mutants may cause disease through different mechanisms that also likely include their selective transdominant effects on co-expressed connexins, highlighting the overall complexity of connexin-linked diseases and the importance of GJIC in disease prevention.

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Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function

Cited by 41 publications

References 42 publications

Newborn genetic screening for hearing impairment: a population-based longitudinal study

Newborn genetic screening for hearing impairment: a population-based longitudinal study

Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation

Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies

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