CaV1.2 I-II linker structure and Timothy syndrome |
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Authors: | Lior Almagor Orna Chomsky-Hecht Adva Ben-Mocha Doran Hendin-Barak Nathan Dascal Joel A Hirsch |
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Institution: | 1.Department of Biochemistry and Molecular Biology; Institute of Structural Biology; George S. Wise Faculty of Life Sciences; Tel Aviv University; Tel Aviv, Israel;2.Department of Physiology and Pharmacology; Sackler Faculty of Medicine; Tel Aviv University; Tel Aviv, Israel |
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Abstract: | CaV channels are multi-subunit protein complexes that enable inward cellular Ca2+ currents in response to membrane depolarization. We recently described structure-function studies of the intracellular α1 subunit domain I-II linker, directly downstream of domain IS6. The results show the extent of the linker’s helical structure to be subfamily dependent, as dictated by highly conserved primary sequence differences. Moreover, the difference in structure confers different biophysical properties, particularly the extent and kinetics of voltage and calcium-dependent inactivation. Timothy syndrome is a human genetic disorder due to mutations in the CaV1.2 gene. Here, we explored whether perturbation of the I-II linker helical structure might provide a mechanistic explanation for a Timothy syndrome mutant’s (human CaV1.2 G406R equivalent) biophysical effects on inactivation and activation. The results are equivocal, suggesting that a full mechanistic explanation for this Timothy syndrome mutation requires further investigation. |
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Keywords: | Timothy syndrome voltage-dependent calcium channels voltage-dependent inactivation α -helix |
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