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Myotonia-related mutations in the distal C-terminus of ClC-1 and ClC-0 chloride channels affect the structure of a poly-proline helix.
Macías MJ
,
Teijido O
,
Zifarelli G
,
Martin P
,
Ramirez-Espain X
,
Zorzano A
,
Palacín M
,
Pusch M
,
Estévez R
.
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Myotonia is a state of hyperexcitability of skeletal-muscle fibres. Mutations in the ClC-1 Cl- channel cause recessive and dominant forms of this disease. Mutations have been described throughout the protein-coding region, including three sequence variations (A885P, R894X and P932L) in a distal C-terminal stretch of residues [CTD (C-terminal domain) region] that are not conserved between CLC proteins. We show that surface expression of these mutants is reduced in Xenopus oocytes compared with wild-type ClC-1. Functional, biochemical and NMR spectroscopy studies revealed that the CTD region encompasses a segment conserved in most voltage-dependent CLC channels that folds with a secondary structure containing a short type II poly-proline helix. We found that the myotonia-causing mutation A885P disturbs this structure by extending the poly-proline helix. We hypothesize that this structural modification results in the observed alteration of the common gate that acts on both pores of the channel. We provide the first experimental investigation of structural changes resulting from myotonia-causing mutations.
Adzhubei,
Left-handed polyproline II helices commonly occur in globular proteins.
1993, Pubmed
Adzhubei,
Left-handed polyproline II helices commonly occur in globular proteins.
1993,
Pubmed
Bartels,
The program XEASY for computer-supported NMR spectral analysis of biological macromolecules.
1995,
Pubmed
Beck,
Molecular basis for decreased muscle chloride conductance in the myotonic goat.
1996,
Pubmed
,
Xenbase
Chen,
Nonequilibrium gating and voltage dependence of the ClC-0 Cl- channel.
1996,
Pubmed
Duffield,
Involvement of helices at the dimer interface in ClC-1 common gating.
2003,
Pubmed
Estévez,
Functional and structural conservation of CBS domains from CLC chloride channels.
2004,
Pubmed
,
Xenbase
Estévez,
CLC chloride channels: correlating structure with function.
2002,
Pubmed
Fong,
Determinants of slow gating in ClC-0, the voltage-gated chloride channel of Torpedo marmorata.
1998,
Pubmed
,
Xenbase
George,
Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita).
1993,
Pubmed
George,
Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita.
1994,
Pubmed
Hebeisen,
Carboxy-terminal truncations modify the outer pore vestibule of muscle chloride channels.
2005,
Pubmed
Hebeisen,
The role of the carboxyl terminus in ClC chloride channel function.
2004,
Pubmed
Hryciw,
Relevance of the D13 region to the function of the skeletal muscle chloride channel, ClC-1.
1998,
Pubmed
Ignoul,
CBS domains: structure, function, and pathology in human proteins.
2005,
Pubmed
Jentsch,
Myotonias due to CLC-1 chloride channel mutations.
1995,
Pubmed
Jentsch,
Physiological functions of CLC Cl- channels gleaned from human genetic disease and mouse models.
2005,
Pubmed
Koch,
The skeletal muscle chloride channel in dominant and recessive human myotonia.
1992,
Pubmed
Koradi,
MOLMOL: a program for display and analysis of macromolecular structures.
1996,
Pubmed
Macias,
WW and SH3 domains, two different scaffolds to recognize proline-rich ligands.
2002,
Pubmed
Maduke,
Formation of CLC-0 chloride channels from separated transmembrane and cytoplasmic domains.
1998,
Pubmed
,
Xenbase
Meyer,
Crystal structure of the cytoplasmic domain of the chloride channel ClC-0.
2006,
Pubmed
Meyer-Kleine,
Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia.
1995,
Pubmed
,
Xenbase
Miller,
Crystal structure of a tandem cystathionine-beta-synthase (CBS) domain protein (TM0935) from Thermotoga maritima at 1.87 A resolution.
2004,
Pubmed
Monks,
Helical structure and packing orientation of the S2 segment in the Shaker K+ channel.
1999,
Pubmed
,
Xenbase
Nagamitsu,
A "dystrophic" variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene.
2000,
Pubmed
Papponen,
Founder mutations and the high prevalence of myotonia congenita in northern Finland.
1999,
Pubmed
Pires,
Structural basis for APPTPPPLPP peptide recognition by the FBP11WW1 domain.
2005,
Pubmed
Pusch,
Myotonia caused by mutations in the muscle chloride channel gene CLCN1.
2002,
Pubmed
Pusch,
Temperature dependence of fast and slow gating relaxations of ClC-0 chloride channels.
1997,
Pubmed
,
Xenbase
Pusch,
Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel.
1995,
Pubmed
Saviane,
The muscle chloride channel ClC-1 has a double-barreled appearance that is differentially affected in dominant and recessive myotonia.
1999,
Pubmed
,
Xenbase
Simpson,
Characterization of three myotonia-associated mutations of the CLCN1 chloride channel gene via heterologous expression.
2004,
Pubmed
,
Xenbase
Yusef,
Removal of gating in voltage-dependent ClC-2 chloride channel by point mutations affecting the pore and C-terminus CBS-2 domain.
2006,
Pubmed
