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首页> 外文期刊>The European Journal of Neuroscience >Modelling of the III-IV loop, a domain involved in calcium channel Cav2.1 inactivation, highlights a structural homology with the gamma subunit of G proteins.
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Modelling of the III-IV loop, a domain involved in calcium channel Cav2.1 inactivation, highlights a structural homology with the gamma subunit of G proteins.

机译：钙通道Cav2.1失活所涉及的结构域III-IV环的建模突出显示了与G蛋白的γ亚基的结构同源性。

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摘要

We have modelled the conformation of the III-IV loop of the Cav2.1 subunit of P/Q calcium channels, a loop that is implicated in fast voltage-dependent inactivation. Change in channel inactivation requires its direct interaction with the I-II loop. This interaction occurs with an affinity in the order of 70 nm. Intracellular injection of a 40-mer III-IV loop-derived peptide produces an increase in the rate of fast inactivation. This alteration in channel kinetic is also accompanied by a hyperpolarizing shift in the steady-state voltage-dependence of inactivation. None of these effects are observed in the presence of a beta subunit, suggesting the existence of a competitive mechanism of action between the beta subunit and the III-IV loop. Amino acid sequence comparison using BLAST reveals that the III-IV loop shares 53% identity with the gamma subunit of G proteins. Because of the pivotal contribution of the III-IV loop to inactivation, an atomic model of the III-IV loop was generated by both homology modelling and molecular mechanics calculations. Using the X-ray structures of the betagamma dimer of the heterotrimeric G-proteins as templates, the III-IV loop is predicted to contain a well-structured alpha-helix at the amino-terminus with both the N- and C-termini having the same orientation in the plane of the inner lipid bilayer. We provide a hypothetical working model in which we propose that the III-IV loop interacts with the I-II loop via its Gbetagamma binding domain.
机译：我们已经模拟了P / Q钙通道的Cav2.1亚基的III-IV环的构象，该环与快速电压依赖性失活有关。通道失活的变化要求它与I-II回路直接交互。这种相互作用的亲和力约为70 nm。胞内注射40-mer III-IV环衍生肽会增加快速失活的速率。通道动力学的这种改变还伴随着灭活的稳态电压依赖性的超极化转变。在β亚基的存在下没有观察到这些作用，表明在β亚基和III-IV环之间存在竞争性作用机制。使用BLAST进行的氨基酸序列比较显示，III-IV环与G蛋白的γ亚基具有53％的同一性。由于III-IV环对失活的关键作用，通过同源性建模和分子力学计算生成了III-IV环的原子模型。使用异三聚体G蛋白的betagamma二聚体的X射线结构作为模板，可以预测III-IV环在氨基端含有结构良好的α-螺旋，而N-和C-末端均具有在内部脂质双层的平面中具有相同的方向。我们提供了一个假设的工作模型，其中我们提出III-IV环通过其Gbetagamma结合域与I-II环相互作用。

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