Abstract
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.
Highlights
The structures of ATP7B metal-binding domains 2–6 have been solved previously by NMR8–10
Mutations that impair transport activity or disrupt intracellular targeting of ATP7B cause Wilson disease, chronic copper toxicosis that primarily affects the liver and the brain
Out of about 300 single amino acid substitutions known to be associated with Wilson disease, only five are located in the MBD1-4 region, and only one of those five, G85V, in MBD1 (Fig. 1)
Summary
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. There is no high-resolution structure of ATP7B, but the structures of most cytosolic domains have been solved by NMR, and the overall structure of ATP7B has been modeled by homology[5] using the X-ray structure of the bacterial copper ATPase CopA from Legionella pneumophila[2] as a template This model does not include the N-terminal chain of the six cytosolic metal-binding domains (MBDs) connected by flexible loops of various length, a unique structural feature of ATP7B and of the closely related copper transporter ATP7A (Fig. 1). The paucity of missense disease mutations in MBD1-4 may reflect the fact that these domains play a regulatory role, and, unlike MBDs 5-6, are not strictly required for copper transport activity. To determine the disruptive mechanism of the G85V mutation, we have solved the structure of MBD1, the last unsolved metal-binding domain of ATP7B
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