Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, Canada.
NMRFAM, University of Wisconsin, Madison, WI, USA.
Sci Rep. 2018 Jan 12;8(1):581. doi: 10.1038/s41598-017-18951-1.
Copper-transporter ATP7B maintains copper homeostasis in the human cells and delivers copper to the biosynthetic pathways for incorporation into the newly synthesized copper-containing proteins. ATP7B is a target of several hundred mutations that lead to Wilson disease, a chronic copper toxicosis. ATP7B contains a chain of six cytosolic metal-binding domains (MBDs), the first four of which (MBD1-4) are believed to be regulatory, and the last two (MBD5-6) are required for enzyme activity. We report the NMR structure of MBD1, the last unsolved metal-binding domain of ATP7B. The structure reveals the disruptive mechanism of G85V mutation, one of the very few disease causing missense mutations in the MBD1-4 region of ATP7B.
铜转运体 ATP7B 维持人类细胞内的铜稳态，并将铜输送到生物合成途径中，以整合到新合成的含铜蛋白质中。ATP7B 是数百种突变的靶点，这些突变导致威尔逊病，一种慢性铜中毒。ATP7B 包含一系列六个胞质金属结合结构域（MBDs），前四个（MBD1-4）被认为是调节的，最后两个（MBD5-6）是酶活性所必需的。我们报告了 ATP7B 的最后一个未解决的金属结合结构域 MBD1 的 NMR 结构。该结构揭示了 G85V 突变的破坏机制，G85V 突变是 ATP7B 的 MBD1-4 区域中极少数致病错义突变之一。
