ATP7B

ATP7B Full Name

ATPase, Cu++ transporting, beta polypeptide

ATP7B Introduction

ATP7B (ATPase, Cu++ transporting, beta polypeptide) is a copper-transporting P-type ATPase that plays a central role in maintaining systemic copper homeostasis, especially in the liver. As an essential membrane transporter, ATP7B contains a conserved P-type ATPase core composed of cytosolic actuator (A), phosphorylation (P), and nucleotide-binding (N) domains, multiple transmembrane copper transport regions, and six N-terminal metal-binding domains that sense intracellular copper levels. ATP7B functions as a molecular "copper regulator" by coupling ATP hydrolysis with copper translocation across cellular membranes, ensuring that copper is properly delivered for biological processes while preventing toxic accumulation. When ATP7B activity is impaired, cells lose the ability to control copper distribution, leading to a progressive imbalance that can affect the liver, brain, and other organs.

The primary physiological function of ATP7B is to regulate copper trafficking in hepatocytes through two copper-dependent mechanisms. Under normal copper availability, ATP7B transports copper into the trans-Golgi network, where copper is incorporated into ceruloplasmin, a major copper-carrying protein in the blood. When intracellular copper levels become excessive, ATP7B relocates toward vesicular compartments and the canalicular membrane to promote biliary copper excretion. Structural studies have revealed that ATP7B contains specialized copper-recognition elements and a coordinated metal transport pathway that enables precise regulation of copper movement. Genetic variants in ATP7B can disrupt copper binding, ATP-dependent phosphorylation, membrane trafficking, protein stability, or subcellular localization, resulting in diverse functional defects rather than a single uniform loss-of-function mechanism.

ATP7B dysfunction is most strongly associated with Wilson disease, an inherited autosomal recessive disorder characterized by abnormal copper accumulation caused by defective copper transport and impaired biliary copper elimination. Wilson disease can present with hepatic injury, neurological symptoms, psychiatric manifestations, and systemic copper toxicity, while the clinical severity varies depending on the type and location of ATP7B mutations. Emerging research suggests that copper overload caused by ATP7B deficiency promotes oxidative stress, mitochondrial dysfunction, neuroinflammation, and impaired cellular homeostasis, contributing to progressive tissue damage. Understanding ATP7B structure, regulation, and mutation-driven functional changes provides important insights for developing improved diagnostic biomarkers, genotype-based disease prediction strategies, and targeted therapeutic approaches for copper metabolism disorders.

Alternate Names for ATP7B

ATP7B; ATPase, Cu++ transporting, beta polypeptide; ATPase, Cu++ transporting, beta polypeptide (Wilson disease); WND; copper-transporting ATPase 2; Wilson disease; copper pump 2; Wilson disease-associated protein; ATPase, Cu(2+)- transporting, beta polypeptide; WD; PWD; WC1; WND;

• 1.Bitter RM, et al.; Structure of the Wilson disease copper transporter ATP7B. Sci Adv. 2022, 8(9):eabl5508.
  2.Ovchinnikova EV, et al.; Epidemiology of Wilson's Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions. Int J Mol Sci. 2024, 25(4):2402.