| Structural highlights
Disease
[CLCN1_HUMAN] Thomsen and Becker disease. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
[CLCN1_HUMAN] Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
ClC-1 protein channels facilitate rapid passage of chloride ions across cellular membranes, thereby orchestrating skeletal muscle excitability. Malfunction of ClC-1 is associated with myotonia congenita, a disease impairing muscle relaxation. Here, we present the cryo-electron microscopy (cryo-EM) structure of human ClC-1, uncovering an architecture reminiscent of that of bovine ClC-K and CLC transporters. The chloride conducting pathway exhibits distinct features, including a central glutamate residue ("fast gate") known to confer voltage-dependence (a mechanistic feature not present in ClC-K), linked to a somewhat rearranged central tyrosine and a narrower aperture of the pore toward the extracellular vestibule. These characteristics agree with the lower chloride flux of ClC-1 compared with ClC-K and enable us to propose a model for chloride passage in voltage-dependent CLC channels. Comparison of structures derived from protein studied in different experimental conditions supports the notion that pH and adenine nucleotides regulate ClC-1 through interactions between the so-called cystathionine-beta-synthase (CBS) domains and the intracellular vestibule ("slow gating"). The structure also provides a framework for analysis of mutations causing myotonia congenita and reveals a striking correlation between mutated residues and the phenotypic effect on voltage gating, opening avenues for rational design of therapies against ClC-1-related diseases.
Structure of the human ClC-1 chloride channel.,Wang K, Preisler SS, Zhang L, Cui Y, Missel JW, Gronberg C, Gotfryd K, Lindahl E, Andersson M, Calloe K, Egea PF, Klaerke DA, Pusch M, Pedersen PA, Zhou ZH, Gourdon P PLoS Biol. 2019 Apr 25;17(4):e3000218. doi: 10.1371/journal.pbio.3000218., eCollection 2019 Apr. PMID:31022181[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ryan A, Rudel R, Kuchenbecker M, Fahlke C. A novel alteration of muscle chloride channel gating in myotonia levior. J Physiol. 2002 Dec 1;545(Pt 2):345-54. PMID:12456816
- ↑ Ulzi G, Lecchi M, Sansone V, Redaelli E, Corti E, Saccomanno D, Pagliarani S, Corti S, Magri F, Raimondi M, D'Angelo G, Modoni A, Bresolin N, Meola G, Wanke E, Comi GP, Lucchiari S. Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients. J Neurol Sci. 2012 Jul 15;318(1-2):65-71. doi: 10.1016/j.jns.2012.03.024. Epub, 2012 Apr 21. PMID:22521272 doi:https://dx.doi.org/10.1016/j.jns.2012.03.024
- ↑ Portaro S, Altamura C, Licata N, Camerino GM, Imbrici P, Musumeci O, Rodolico C, Conte Camerino D, Toscano A, Desaphy JF. Clinical, Molecular, and Functional Characterization of CLCN1 Mutations in Three Families with Recessive Myotonia Congenita. Neuromolecular Med. 2015 Sep;17(3):285-96. doi: 10.1007/s12017-015-8356-8. Epub, 2015 May 26. PMID:26007199 doi:https://dx.doi.org/10.1007/s12017-015-8356-8
- ↑ Ronstedt K, Sternberg D, Detro-Dassen S, Gramkow T, Begemann B, Becher T, Kilian P, Grieschat M, Machtens JP, Schmalzing G, Fischer M, Fahlke C. Impaired surface membrane insertion of homo- and heterodimeric human muscle chloride channels carrying amino-terminal myotonia-causing mutations. Sci Rep. 2015 Oct 27;5:15382. doi: 10.1038/srep15382. PMID:26502825 doi:https://dx.doi.org/10.1038/srep15382
- ↑ Vindas-Smith R, Fiore M, Vasquez M, Cuenca P, Del Valle G, Lagostena L, Gaitan-Penas H, Estevez R, Pusch M, Morales F. Identification and Functional Characterization of CLCN1 Mutations Found in Nondystrophic Myotonia Patients. Hum Mutat. 2016 Jan;37(1):74-83. doi: 10.1002/humu.22916. Epub 2015 Oct 28. PMID:26510092 doi:https://dx.doi.org/10.1002/humu.22916
- ↑ Lorenz C, Meyer-Kleine C, Steinmeyer K, Koch MC, Jentsch TJ. Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum Mol Genet. 1994 Jun;3(6):941-6. PMID:7951242
- ↑ Steinmeyer K, Lorenz C, Pusch M, Koch MC, Jentsch TJ. Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). EMBO J. 1994 Feb 15;13(4):737-43. PMID:8112288
- ↑ Fahlke C, Beck CL, George AL Jr. A mutation in autosomal dominant myotonia congenita affects pore properties of the muscle chloride channel. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2729-34. PMID:9122265
- ↑ Kubisch C, Schmidt-Rose T, Fontaine B, Bretag AH, Jentsch TJ. ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence. Hum Mol Genet. 1998 Oct;7(11):1753-60. PMID:9736777
- ↑ Wang K, Preisler SS, Zhang L, Cui Y, Missel JW, Gronberg C, Gotfryd K, Lindahl E, Andersson M, Calloe K, Egea PF, Klaerke DA, Pusch M, Pedersen PA, Zhou ZH, Gourdon P. Structure of the human ClC-1 chloride channel. PLoS Biol. 2019 Apr 25;17(4):e3000218. doi: 10.1371/journal.pbio.3000218., eCollection 2019 Apr. PMID:31022181 doi:https://dx.doi.org/10.1371/journal.pbio.3000218
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