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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes
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Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes

机译：ABCC8核苷酸结合结构域2的精氨酸1380突变产生的ATPase活性增加导致新生儿糖尿病

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摘要

Gain-of-function mutations in the genes encoding the ATP-sensitive potassium (K_(ATP)) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are a common cause of neonatal diabetes mellitus. Here we investigate the molecular mechanism by which two heterozygous mutations in the second nucleotide-binding domain (NBD2) of SUR1 (R1380L and R1380C) separately cause neonatal diabetes. SUR1 is a channel regulator that modulates the gating of the pore formed by Kir6.2. K_(ATP) channel activity is inhibited by ATP binding to Kir6.2 but is stimulated by MgADP binding, or by MgATP binding and hydrolysis, at the NBDs of SUR1. Functional analysis of purified NBD2 showed that each mutation enhances MgATP hydrolysis by purified isolated fusion proteins of maltose-binding protein and NBD2. Inhibition of ATP hydrolysis by MgADP was unaffected by mutation of R1380, but inhibition by beryllium fluoride (which traps the ATPase cycle in the prehydrolytic state) was reduced. MgADP-dependent activation of Katp channel activity was unaffected. These data suggest that the R1380L and R1380C mutations enhance the off-rate of Pi, thereby enhancing the hydrolytic rate. Molecular modeling studies supported this idea. Because mutant channels were inhibited less strongly by MgATP, this would increase K_(ATP) currents in pancreatic beta cells, thus reducing insulin secretion and producing diabetes.
机译：编码ATP敏感钾（K_（ATP））通道亚基Kir6.2（KCNJ11）和SUR1（ABCC8）的基因中的功能获得性突变是新生儿糖尿病的常见原因。在这里，我们研究了SUR1（R1380L和R1380C）的第二个核苷酸结合域（NBD2）中的两个杂合突变分别引起新生儿糖尿病的分子机制。 SUR1是一种通道调节剂，可调节Kir6.2形成的孔的门控。 ATP与Kir6.2结合会抑制K_（ATP）通道活性，但在SUR1的NBD处会受到MgADP结合或MgATP结合和水解的刺激。纯化的NBD2的功能分析表明，每个突变均可通过纯化的分离的麦芽糖结合蛋白和NBD2融合蛋白来增强MgATP水解。 MgADP对ATP水解的抑制作用不受R1380突变的影响，但氟化铍（在预水解状态下捕获ATPase循环）的抑制作用降低了。 MgADP依赖的Katp通道活性的激活不受影响。这些数据表明，R1380L和R1380C突变提高了Pi的解离速率，从而提高了水解速率。分子模型研究支持了这一想法。由于MgATP对突变通道的抑制作用较弱，因此会增加胰腺β细胞中的K_（ATP）电流，从而减少胰岛素分泌并产生糖尿病。

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