Molecular Modeling of the Structural and Dynamical Changes in Calcium Channel TRPV5 Induced by the African-Specific A563T Variation.
Molecular Modeling of the Structural and Dynamical Changes in Calcium Channel TRPV5 Induced by the African-Specific A563T Variation.
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DOI：
10.1021/acs.biochem.5b00732
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发表时间：
2016-03-01
期刊：
影响因子：
2.9
通讯作者：
Peng JB
中科院分区：
文献类型：
--
作者：
Wang L;Holmes RP;Peng JB
TRPV5（瞬时受体电位阳离子通道，香草酸亚家族，成员 5）在肾脏主动 Ca2+ 重吸收中发挥关键作用。 TRPV5 的变异在非洲人群中发生频率很高，可能有助于提高 Ca2+ 重吸收效率。 A563T 是非洲特有的变异之一，表现出增强的 Ca2+ 转运能力。然而，尚不清楚这种变化如何影响通道孔隙。基于TRPV1的结构，生成了TRPV5模型来模拟A563T变异引起的结构和动力学变化。基于该模型，氨基酸残基563与V540相互作用，V540距离参与Ca2+选择性和Mg2+阻断的关键残基D542仅一个残基。 A563T 变体增加了二级结构的稳定性并减少了 D542 的动态运动。此外，A563T 变体改变了孔外表面的静电势。在另一个由TRPV5和TRPV1之间的选择性过滤器中的替代排列衍生的模型中也观察到选择性过滤器残留物和残留物563之间的接触以及两个TRPV5变体之间的静电电位的差异。这些发现表明，A563T 变异引起 TRPV5 孔的结构、动力学和静电变化，为与 A563T 变异相关的功能改变提供了结构上的见解。
TRPV5 (Transient Receptor Potential cation channels, Vanilloid subfamily, member 5) plays a key role in active Ca2+ reabsorption in the kidney. Variations in TRPV5 occur at high frequency in African populations and may contribute to their higher efficiency in Ca2+ reabsorption. One of the African specific variations, A563T, exhibits increased Ca2+ transport ability. However, it is unclear how this variation influences the channel pore. Based on the structure of TRPV1, a TRPV5 model was generated to simulate the structural and dynamical changes induced by the A563T variation. Based on this model, amino-acid residue 563 interacts with V540, which is one residue away from the key residue D542 involved in Ca2+ selectivity and Mg2+ blockade. The A563T variation increases secondary structure stability and reduces dynamical motion of D542. In addition, the A563T variation alters electrostatic potential of the outer surface of the pore. Differences in contact between selective filter residues and residue 563 and in electrostatic potential between the two TRPV5 variants were also observed in another model derived from an alternative alignment in the selective filters between TRPV5 and TRPV1. These findings indicate that the A563T variation induces structural, dynamical, and electrostatic changes in the TRPV5 pore, providing a structural insight into the functional alterations associated with the A563T variation.