Department of Biochemistry and Molecular Biology, Institute of Structural Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Channels (Austin). 2012 Nov-Dec;6(6):468-72. doi: 10.4161/chan.22078. Epub 2012 Sep 18.
Ca(V) channels are multi-subunit protein complexes that enable inward cellular Ca(2+) 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 Ca(V)1.2 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 Ca(V)1.2 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.
钙通道是多亚基蛋白复合物，能够在膜去极化时产生内向细胞钙电流。我们最近描述了细胞内α1 亚基结构域 I-II 接头的结构-功能研究，该接头直接位于结构域 IS6 的下游。结果表明，接头的螺旋结构的程度取决于亚家族，这是由高度保守的一级序列差异决定的。此外，结构的差异赋予了不同的生物物理特性，特别是电压和钙依赖性失活的程度和动力学。 Timothy 综合征是一种由于钙通道（CaV）1.2 基因突变引起的人类遗传疾病。在这里，我们探讨了 I-II 接头螺旋结构的扰动是否可能为 Timothy 综合征突变体（人类 CaV1.2 G406R 等效物）对失活和激活的生物物理效应提供机制解释。结果是模棱两可的，这表明需要进一步研究才能对这种 Timothy 综合征突变提供完整的机制解释。
