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.
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April 2007
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Research Article|
March 13 2007
Myotonia-related mutations in the distal C-terminus of ClC-1 and ClC-0 chloride channels affect the structure of a poly-proline helix
María J. Macías
;
María J. Macías
1
*Institut de Recerca Biomédica, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona, E-08028, Spain
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Oscar Teijido
;
Oscar Teijido
1
†Departament de Bioquímica i Biología Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, Barcelona, E-08028, Spain
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Giovanni Zifarelli
;
Giovanni Zifarelli
‡Istituto di Biofisica, Via de Marini 6, I-16149 Genova, Italy
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Pau Martin
;
Pau Martin
*Institut de Recerca Biomédica, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona, E-08028, Spain
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Ximena Ramirez-Espain
;
Ximena Ramirez-Espain
*Institut de Recerca Biomédica, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona, E-08028, Spain
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Antonio Zorzano
;
Antonio Zorzano
*Institut de Recerca Biomédica, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona, E-08028, Spain
†Departament de Bioquímica i Biología Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, Barcelona, E-08028, Spain
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Manuel Palacín
;
Manuel Palacín
*Institut de Recerca Biomédica, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona, E-08028, Spain
†Departament de Bioquímica i Biología Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, Barcelona, E-08028, Spain
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Michael Pusch
;
Michael Pusch
‡Istituto di Biofisica, Via de Marini 6, I-16149 Genova, Italy
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Raúl Estévez
Raúl Estévez
2
*Institut de Recerca Biomédica, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona, E-08028, Spain
†Departament de Bioquímica i Biología Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, Barcelona, E-08028, Spain
§ZMNH (Zentrum für Molekulare Neurobiologie Hamburg), Hamburg University, Falkenried 94, D-20246 Hamburg, Germany
2To whom correspondence should be addressed (email restevez@pcb.ub.es).
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Biochem J (2007) 403 (1): 79–87.
Article history
Received:
August 10 2006
Revision Received:
November 06 2006
Accepted:
November 15 2006
Accepted Manuscript online:
November 15 2006
Citation
María J. Macías, Oscar Teijido, Giovanni Zifarelli, Pau Martin, Ximena Ramirez-Espain, Antonio Zorzano, Manuel Palacín, Michael Pusch, Raúl Estévez; Myotonia-related mutations in the distal C-terminus of ClC-1 and ClC-0 chloride channels affect the structure of a poly-proline helix. Biochem J 1 April 2007; 403 (1): 79–87. doi: https://doi.org/10.1042/BJ20061230
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