Copper is essential for normal human metabolism. Inborn defects in function of proteins distributing copper within the body lead to severe metabolic disorders, such as Menkes disease and Wilson disease, which are characterized by neurological and hepatic abnormalities, renal and vascular damage. The copper transporting ATPases, ATP7A (Menkes disease protein) and ATP7B (Wilson disease protein), have been identified as key regulators of copper concentration in human cells. In recent years, information on biochemical and intracellular properties of these transporters has been rapidly generated. However, little is known about the distinct physiological roles of ATP7A and ATP7B. Our long term goal is to characterize specific roles of ATP7A and ATP7B in copper homeostasis as a prerequisite to the development and improvement of therapeutic treatments for these disorders. The major goal of this proposal is to understand specific roles of ATP7A and ATP7B in copper transport. Using recombinant protein construction, site directed mutagenesis, segment exchanging experiments, and copper binding affinity assays; we will determine the role of a unique sequence insert in the function and trafficking of ATP7A and ATP7B. Also, we will investigate the role of acceptor proteins on copper release by measuring the rate of copper transport of ATP7A after overexpression or knock-down of peptidyl-a-monooxygenase. Finally, we will examine the ? dependence of ATP7B activity on CIC-4, a mammalian endosomal CI-/H+ exchanger with poorly understood function in cell physiology. The result of the proposed research will yield information essential for understanding and better treatment of Menkes disease and Wilson disease. ?

Public Health Relevance

Menkes disease and Wilson disease are characterized by neurological and hepatic abnormalities, renal and vascular damage, and are caused by a disruption in function of the enzymes ATP7A and ATP7B, respectively. Our goal is to characterize the specific roles of ATP7A and ATP7B as a prerequisite to the development and improvement of therapeutic treatments for these disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK077429-01A1
Application #
7613654
Study Section
Special Emphasis Panel (ZRG1-F04B-P (20))
Program Officer
Podskalny, Judith M,
Project Start
2008-09-29
Project End
2009-09-28
Budget Start
2008-09-29
Budget End
2009-09-28
Support Year
1
Fiscal Year
2008
Total Cost
$44,846
Indirect Cost
Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Barry, Amanda N; Otoikhian, Adenike; Bhatt, Sujata et al. (2011) The lumenal loop Met672-Pro707 of copper-transporting ATPase ATP7A binds metals and facilitates copper release from the intramembrane sites. J Biol Chem 286:26585-94
Barry, Amanda N; Shinde, Ujwal; Lutsenko, Svetlana (2010) Structural organization of human Cu-transporting ATPases: learning from building blocks. J Biol Inorg Chem 15:47-59