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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations
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Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations

机译：威尔逊病蛋白N域的解决方案结构：不同的核苷酸结合环境和疾病突变的影响。

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摘要

Wilson disease protein (ATP7B) is a copper-transporting P-1B-type ATPase that regulates copper homeostasis and biosynthesis of copper-containing enzymes in human tissues. Inactivation of ATP7B or related ATP7A leads to severe neurodegenerative disorders, whereas their overexpression contributes to cancer cell resistance to chemotherapeutics. Copper-transporting ATPases differ from other P-type ATPases in their topology and the sequence of their nucleotide-binding domain (N-domain). To gain insight into the structural basis of ATP7B function, we have solved the structure of the ATP7B N-domain in the presence of ATP by using heteronuclear multidimensional NMR spectroscopy. The N-domain consists of a six-stranded beta-sheet with two adjacent alpha-helical hairpins and, unexpectedly, shows higher similarity to the bacterial K+-transporting ATPase KdpB than to the mammalian Ca2+-ATPase or Na+,K+-ATPase. The common core structure of P-type ATPases is retained in the 3D fold of the N-domain; however, the nucleotide coordination environment of ATP7B within this fold is different. The residues H1069, 61099, 61101, 11102, 61149, and N1150 conserved in the P-1B-ATPase subfamily contribute to ATP binding. Analysis of the frequent disease mutation H1069Q demonstrates that this mutation does not significantly affect the structure of the N-domain but prevents tight binding of ATP. The structure of the N-domain accounts for the disruptive effects of > 30 known Wilson disease mutations. The unique features of the N-domain provide a structural basis for the development of specific inhibitors and regulators of ATP7B.
机译：威尔逊病蛋白（ATP7B）是一种铜转运P-1B型ATPase，它调节人体组织中的铜稳态和含铜酶的生物合成。 ATP7B或相关ATP7A的失活会导致严重的神经退行性疾病，而它们的过度表达则有助于癌细胞对化学疗法的抵抗。铜转运ATP酶的拓扑结构和核苷酸结合结构域（N结构域）的序列与其他P型ATP酶不同。为了深入了解ATP7B功能的结构基础，我们使用异核多维NMR光谱法解决了ATP存在下ATP7B N域的结构。 N结构域由具有两个相邻α-螺旋发夹的六链β-折叠组成，并且出乎意料的是，与细菌K +转运ATPase KdpB的相似性高于与哺乳动物Ca2 + -ATPase或Na +，K + -ATPase的相似性。 P型ATP酶的共同核心结构保留在N结构域的3D折叠中。但是，此折叠范围内ATP7B的核苷酸配位环境不同。 P-1B-ATPase亚家族中保守的残基H1069、61099、61101、11102、61149和N1150有助于ATP结合。对常见疾病突变H1069Q的分析表明，该突变不会显着影响N结构域的结构，但会阻止ATP的紧密结合。 N结构域解释了> 30种已知的Wilson疾病突变的破坏作用。 N结构域的独特功能为开发ATP7B的特定抑制剂和调节剂提供了结构基础。

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