A Gly-zipper motif mediates homodimerization of the transmembrane domain of the mitochondrial kinase ADCK3.
A Gly-zipper motif mediates homodimerization of the transmembrane domain of the mitochondrial kinase ADCK3.
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DOI：
10.1021/ja505017f
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发表时间：
2014-10-08
影响因子：
15
通讯作者：
Senes, Alessandro
中科院分区：
文献类型：
--
作者：
Khadria, Ambalika S.;Mueller, Benjamin K.;Stefely, Jonathan A.;Tan, Chin Huat;Pagliarini, David J.;Senes, Alessandro
脂双层疏水环境中 α 螺旋之间的相互作用对于跨膜蛋白的折叠和功能是不可或缺的；然而，调节这些相互作用的主要力量仍然存在争议，而且我们预测这些相互作用的能力在很大程度上仍然未经测试。我们最近证明，频繁的跨膜关联基序 GASright，即血型糖蛋白 A 二聚体的包含 GxxxG 的折叠，最适合形成 Cα-H 氢键扩展网络，支持了这些键是关联的主要贡献者的假设。我们还发现，Cα-H 氢键和螺旋间堆积的优化足以在近原子水平上通过计算预测已知 GASright 二聚体的结构。在这里，我们证明这种计算方法可以通过预测和验证线粒体激酶 ADCK3 的跨膜二聚体来表征以前未知的二聚化蛋白质的结构。 ADCK3 参与氧化还原活性脂质、泛醌的生物合成，人类 ADCK3 突变会导致与泛醌缺乏相关的小脑共济失调，但 ADCK3 的生化功能在很大程度上仍不清楚。我们的实验分析表明，ADCK3 的跨膜螺旋寡聚化，具有基于扩展的 Gly-拉链基序的界面，正如我们的模型所预测的那样。这些数据为以下假设提供了强有力的证据：Cα-H 氢键的优化是跨膜螺旋缔合的重要因素。这项工作还为研究跨膜关联在调节 ADCK3 生物活性中的作用提供了结构基础。
Interactions between α-helices within the hydrophobic environment of lipid bilayers are integral to the folding and function of transmembrane proteins; however, the major forces that mediate these interactions remain debated, and our ability to predict these interactions is still largely untested. We recently demonstrated that the frequent transmembrane association motif GASright, the GxxxG-containing fold of the glycophorin A dimer, is optimal for the formation of extended networks of Cα–H hydrogen bonds, supporting the hypothesis that these bonds are major contributors to association. We also found that optimization of Cα–H hydrogen bonding and interhelical packing is sufficient to computationally predict the structure of known GASright dimers at near atomic level. Here, we demonstrate that this computational method can be used to characterize the structure of a protein not previously known to dimerize, by predicting and validating the transmembrane dimer of ADCK3, a mitochondrial kinase. ADCK3 is involved in the biosynthesis of the redox active lipid, ubiquinone, and human ADCK3 mutations cause a cerebellar ataxia associated with ubiquinone deficiency, but the biochemical functions of ADCK3 remain largely undefined. Our experimental analyses show that the transmembrane helix of ADCK3 oligomerizes, with an interface based on an extended Gly-zipper motif, as predicted by our models. The data provide strong evidence for the hypothesis that optimization of Cα–H hydrogen bonding is an important factor in the association of transmembrane helices. This work also provides a structural foundation for investigating the role of transmembrane association in regulating the biological activity of ADCK3.
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DOI：
10.1016/j.bbalip.2013.12.017
发表时间：
2014-04-04
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
He CH;Xie LX;Allan CM;Tran UC;Clarke CF
通讯作者：
Clarke CF
影响因子：
5.6
作者：
Fleming, KG
通讯作者：
Fleming, KG
影响因子：
5.6
作者：
Herrmann, Jana R.;Fuchs, Angelika;Langosch, Dieter
通讯作者：
Langosch, Dieter
DOI：
10.1007/978-1-62703-583-5_3
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Hong H;Chang YC;Bowie JU
通讯作者：
Bowie JU
影响因子：
56.9
作者：
HARBURY, PB;ZHANG, T;ALBER, T
通讯作者：
ALBER, T