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首页> 外文期刊>Biochemistry >Andersen's syndrome mutation effects on the structure and assembly of the cytoplasmic domains of Kir2.1
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Andersen's syndrome mutation effects on the structure and assembly of the cytoplasmic domains of Kir2.1

机译：Andersen综合征突变对Kir2.1胞质域结构和组装的影响

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Kir2.1 channels play a key role in maintaining the correct resting potential in eukaryotic cells. Recently, specific amino acid mutations in the Kir2.1 inwardly rectifying potassium channel have been found to cause Andersen's Syndrome in humans. Here, we have characterized individual Andersen's Syndrome mutants R218Q, G300V, E303K, and Delta 314-315 and have found multiple effects on the ability of the cytoplasmic domains in Kir2.1 channels to form proper tetrameric assemblies. For the R218Q mutation, we identified a second site mutation (T309K) that restored tetrameric assembly but not function. We successfully crystallized and solved the structure ( at 2.0 angstrom) of the N- and C-terminal cytoplasmic domains of Kir2.1-R218Q/T309KS. This new structure revealed multiple conformations of the G-loop and CD loop, providing an explanation for channels that assemble but do not conduct ions. Interestingly, Glu303 forms both intra- and intersubunit salt bridges, depending on the conformation of the G-loop, suggesting that the E303K mutant stabilizes both closed and open G-loop conformations. In the Kir2.1-R218Q/T309KS structure, we discovered that the DE loop forms a hydrophobic pocket that binds 2-methyl-2,4-pentanediol, which is located near the putative G(beta gamma)-activation site of Kir3 channels. Finally, we observed a potassium ion bound to the cytoplasmic domain for this class of K+ channels.
机译：Kir2.1通道在维持真核细胞中正确的静息潜能方面起着关键作用。最近，已发现Kir2.1内向整流钾通道中的特定氨基酸突变会导致人类安徒生综合症。在这里，我们表征了单个Andersen综合征突变体R218Q，G300V，E303K和Delta 314-315，并发现了对Kir2.1通道中胞质域形成适当四聚体组装体能力的多重影响。对于R218Q突变，我们确定了第二个位点突变（T309K），该突变恢复了四聚体装配但没有功能。我们成功地结晶并解决了Kir2.1-R218Q / T309KS的N和C末端胞质域的结构（在2.0埃处）。这种新结构揭示了G环和CD环的多种构象，为组装但不传导离子的通道提供了解释。有趣的是，根据G环的构型，Glu303既可形成亚单位内的盐桥，又可形成亚单位间的盐桥，这表明E303K突变体可稳定闭合的G环和开放的G环构象。在Kir2.1-R218Q / T309KS结构中，我们发现DE环形成一个与2-甲基-2,4-戊二醇结合的疏水口袋，该口袋位于Kir3通道的假定G（βγ）活化位点附近。最后，我们观察到与此类K +通道的胞质域结合的钾离子。

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