ABSTRACT
Copper is an important micronutrient that is used as a cofactor by the enzymes involved in the development and proper function of the central nervous system, the formation of connective tissue and blood vessels, pigmentation, respiration, the detoxification of reactive oxygen species, and many other physiological processes. Dietary copper is absorbed primarily through the small intestine and then utilized throughout the body by all cells and tissues. A large fraction (about 40%) of absorbed
Wilson’s Disease (WD) Protein Is Essential for Homeostatic Control of Copper in Humans ............................................................................................. 145 ATP7B Is a Cu-Transporting P-Type ATPase ........................................................ 146 Functional Expression of ATP7B ........................................................................... 149 Structural Studies of ATP7B .................................................................................. 151
The N-Domain Contains Determinants for Nucleotide Selectivity, Binding, and Orientation ................................................................................... 152 The P-Domain Houses Catalytic Aspartate and Mg2+ ....................................... 154 The A-Domain Facilitates Dephosphorylation .................................................. 154 Cytosolic Domains Communicate during Catalytic Cycle ............................... 155
Protein-Mediated Copper-Transfer May be Unique Feature of P1B-ATPases Mechanism ...................................................................................156 Intracellular Localization and Trafficking of ATP7B ............................................. 157 Wilson’s Disease-Causing Mutations: Known and Predicted Consequences ........ 158
Many Mutations in ATP-Binding Domain Affect Residues in ATP Vicinity ................................................................................... 158 His1069Gln Affects Protein Dynamics and the Placement of ATP in the Binding Pocket ........................................................................................159 WD-Causing Mutations in the A-Domain......................................................... 160 COMMD1 Interactions with ATP7B Are Enhanced by WD Mutations ........... 160
References .............................................................................................................. 161
dietary copper is taken by the liver, which is the main organ regulating copper homeostasis in the human body. Liver uses copper for its metabolic needs and for the biosynthesis of copper-dependent ferroxidase ceruloplasmin (CP). Copper-bound CP is excreted into the blood (Terada et al. 1998), where it accounts for over 60% of total serum copper content. Elevation of hepatic copper results in the activation of the copper excretion mechanism and the export of excess copper into the bile (Terada et al. 1999). The biliary excretion of copper is the major route for regulation of copper content in the body.
