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Arch Biochem Biophys
2016 Oct 15;608:8-19. doi: 10.1016/j.abb.2016.06.019.
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Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using (1)H NMR spectroscopy.
Batir Y
,
Bargiello TA
,
Dowd TL
.
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Alterations in gap junctions underlie the etiologies of syndromic deafness (KID) and Charcot-Marie Tooth disease (CMTX). Functional gap junctions are composed of connexin molecules with N-termini containing a flexible turn around G12, inserting the N-termini into the channel pore allowing voltage gating. The loss of this turn correlates with loss of Connexin 32 (Cx32) function by impaired trafficking to the cell membrane. Using (1)H NMR we show the N-terminus of a syndromic deafness mutation Cx26G12R, producing "leaky channels", contains a turn around G12 which is less structured and more flexible than wild-type. In contrast, the N-terminal structure of the same mutation in Cx32 chimera, Cx32*43E1G12R shows a larger constricted turn and no membrane current expression but forms membrane inserted hemichannels. Their function was rescued by formation of heteromeric channels with wild type subunits. We suggest the inflexible Cx32G12R N-terminus blocks ion conduction in homomeric channels and this channel block is relieved by incorporation of wild type subunits. In contrast, the increased open probability of Cx26G12R hemichannels is likely due to the addition of positive charge in the channel pore changing pore electrostatics and impairing hemichannel regulation by Ca(2+). These results provide mechanistic information on aberrant channel activity observed in disease.
Abrams,
Gap junctions in inherited human disorders of the central nervous system.
2012, Pubmed
Abrams,
Gap junctions in inherited human disorders of the central nervous system.
2012,
Pubmed
Abrams,
GJB1-associated X-linked Charcot-Marie-Tooth disease, a disorder affecting the central and peripheral nervous systems.
2015,
Pubmed
Adler,
The structure of a 19-residue fragment from the C-loop of the fourth epidermal growth factor-like domain of thrombomodulin.
1995,
Pubmed
Babst,
Quality control: quality control at the plasma membrane: one mechanism does not fit all.
2014,
Pubmed
Bennett,
New roles for astrocytes: gap junction hemichannels have something to communicate.
2003,
Pubmed
Bennett,
An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels.
2016,
Pubmed
Bennett,
Electrical coupling and neuronal synchronization in the Mammalian brain.
2004,
Pubmed
Bergoffen,
Connexin mutations in X-linked Charcot-Marie-Tooth disease.
1993,
Pubmed
Brünger,
Crystallography & NMR system: A new software suite for macromolecular structure determination.
1998,
Pubmed
Bukauskas,
Gap junction channel gating.
2004,
Pubmed
Chen,
Cellular strategies of protein quality control.
2011,
Pubmed
Delaglio,
NMRPipe: a multidimensional spectral processing system based on UNIX pipes.
1995,
Pubmed
Deschênes,
Altered trafficking of mutant connexin32.
1997,
Pubmed
Dobrowolski,
Connexin-caused genetic diseases and corresponding mouse models.
2009,
Pubmed
Dyson,
Conformational preferences of synthetic peptides derived from the immunodominant site of the circumsporozoite protein of Plasmodium falciparum by 1H NMR.
1990,
Pubmed
García,
Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.
2015,
Pubmed
Gerido,
Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness.
2007,
Pubmed
,
Xenbase
Johnson,
NMR View: A computer program for the visualization and analysis of NMR data.
1994,
Pubmed
Kalmatsky,
Structural studies of N-terminal mutants of connexin 32 using (1)H NMR spectroscopy.
2012,
Pubmed
Kalmatsky,
Structural studies of the N-terminus of Connexin 32 using 1H NMR spectroscopy.
2009,
Pubmed
Katragadda,
Assembly of a polytopic membrane protein structure from the solution structures of overlapping peptide fragments of bacteriorhodopsin.
2001,
Pubmed
Katragadda,
Solution structure of the loops of bacteriorhodopsin closely resembles the crystal structure.
2000,
Pubmed
Kjaergaard,
Random coil chemical shift for intrinsically disordered proteins: effects of temperature and pH.
2011,
Pubmed
Kjaergaard,
Sequence correction of random coil chemical shifts: correlation between neighbor correction factors and changes in the Ramachandran distribution.
2011,
Pubmed
Kleopa,
How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease?
2012,
Pubmed
Koegel,
Expression and biological significance of Ca2+-activated ion channels in human keratinocytes.
2001,
Pubmed
Koradi,
MOLMOL: a program for display and analysis of macromolecular structures.
1996,
Pubmed
Kwon,
Molecular dynamics simulations of the Cx26 hemichannel: evaluation of structural models with Brownian dynamics.
2011,
Pubmed
,
Xenbase
Kwon,
Voltage-dependent gating of the Cx32*43E1 hemichannel: conformational changes at the channel entrances.
2013,
Pubmed
,
Xenbase
Kwon,
Molecular dynamics simulations of the Cx26 hemichannel: insights into voltage-dependent loop-gating.
2012,
Pubmed
Lee,
Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes.
2009,
Pubmed
,
Xenbase
Levit,
Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases.
2015,
Pubmed
Locke,
Post-translational modifications of connexin26 revealed by mass spectrometry.
2009,
Pubmed
Lopez,
Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N/Y).
2013,
Pubmed
,
Xenbase
Ma,
Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability.
2012,
Pubmed
,
Xenbase
Maeda,
Structure of the connexin 26 gap junction channel at 3.5 A resolution.
2009,
Pubmed
Martínez,
Gap-junction channels dysfunction in deafness and hearing loss.
2009,
Pubmed
Merutka,
'Random coil' 1H chemical shifts obtained as a function of temperature and trifluoroethanol concentration for the peptide series GGXGG.
1995,
Pubmed
Oh,
Changes in permeability caused by connexin 32 mutations underlie X-linked Charcot-Marie-Tooth disease.
1997,
Pubmed
,
Xenbase
Oh,
Determinants of gating polarity of a connexin 32 hemichannel.
2004,
Pubmed
,
Xenbase
Oh,
Stoichiometry of transjunctional voltage-gating polarity reversal by a negative charge substitution in the amino terminus of a connexin32 chimera.
2000,
Pubmed
,
Xenbase
Pfahnl,
A chimeric connexin forming gap junction hemichannels.
1997,
Pubmed
,
Xenbase
Piotto,
Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions.
1992,
Pubmed
Potolicchio,
Connexin-dependent signaling in neuro-hormonal systems.
2012,
Pubmed
Purnick,
Structure of the amino terminus of a gap junction protein.
2000,
Pubmed
,
Xenbase
Purnick,
Reversal of the gating polarity of gap junctions by negative charge substitutions in the N-terminus of connexin 32.
2000,
Pubmed
,
Xenbase
Retamal,
Opening of pannexin- and connexin-based channels increases the excitability of nodose ganglion sensory neurons.
2014,
Pubmed
Sanchez,
Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss.
2014,
Pubmed
Sanchez,
Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome.
2014,
Pubmed
,
Xenbase
Sanchez,
The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions.
2013,
Pubmed
,
Xenbase
Sánchez,
Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome.
2010,
Pubmed
,
Xenbase
Scott,
Connexins in epidermal homeostasis and skin disease.
2012,
Pubmed
,
Xenbase
Siebert,
Structural and functional similarities of calcium homeostasis modulator 1 (CALHM1) ion channel with connexins, pannexins, and innexins.
2013,
Pubmed
Snoeckx,
GJB2 mutations and degree of hearing loss: a multicenter study.
2005,
Pubmed
Terrinoni,
Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation.
2010,
Pubmed
Trexler,
Voltage gating and permeation in a gap junction hemichannel.
1996,
Pubmed
,
Xenbase
Verselis,
Opposite voltage gating polarities of two closely related connexins.
1994,
Pubmed
,
Xenbase
Wishart,
Chemical shifts as a tool for structure determination.
1994,
Pubmed
