The major goal of this project is to understand the molecular and cellular mechanisms that regulate the transport and distribution of copper in human cells. Copper is essential for normal growth and development of human organisms. Copper misbalance results in severe multi-system disorders exemplified by Menkes disease and Wilson's disease. The genes affected in Menkes disease and Wilson's disease code for the copper-transporting ATPases ATP7A and ATP7B, respectively. The copper-transporting ATPases play a central role in human copper homeostasis by delivering copper to the copper-dependent enzymes as well as exporting excess copper from cells. The activity of copper- ATPases is tightly regulated at the molecular and cellular level. The molecular mechanism of this regulation is poorly understood and will be elucidated in the proposed series of experiemnts, which have four specific aims.
Aim 1 will compare the regulation of ATP7A and ATP7B by the copper chaperone Atox1.
Aim 2 will determine the role of oxidation/reduction for the copper-ATPase activity.
Aim 3 is designed to understand the role of a kinase-mediated phosphorylation in modulating the Cu- ATPases activity and intracellular localization.
Aim 4 will characterize a series of Wilson's disease causing mutations to dissect their molecular and cellular consequences. The results will clarify the relative contribution of each copper-ATPase to cellular copper balance as well as the biochemical basis for incomplete compensation of one copper-ATPase by the other in disease. New tools for the analysis of copper transporters in cells will be developed. The results of this research will contribute to the development of better diagnostics and treatments for human disorders of copper metabolism.
The project focuses on understanding the function and regulation of human copper transporters ATP7A and ATP7B, associated with Menkes disease and Wilson's disease, respectively. The studies will identify factors that modulate the activity of the copper transporters in cells and characterize the consequences of known disease- causing mutations. The results will contribute to improved diagnostic and treatment of human disorders of copper metabolism.
|Lutsenko, Svetlana (2014) Modifying factors and phenotypic diversity in Wilson's disease. Ann N Y Acad Sci 1315:56-63|
|Hatori, Yuta; Lutsenko, Svetlana (2013) An expanding range of functions for the copper chaperone/antioxidant protein Atox1. Antioxid Redox Signal 19:945-57|
|Polishchuk, Roman; Lutsenko, Svetlana (2013) Golgi in copper homeostasis: a view from the membrane trafficking field. Histochem Cell Biol 140:285-95|
|Huster, Dominik; Kuhne, Angelika; Bhattacharjee, Ashima et al. (2012) Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology 142:947-956.e5|
|Dmitriev, Oleg Y; Bhattacharjee, Ashima; Nokhrin, Sergiy et al. (2011) Difference in stability of the N-domain underlies distinct intracellular properties of the E1064A and H1069Q mutants of copper-transporting ATPase ATP7B. J Biol Chem 286:16355-62|
|Gupta, Arnab; Bhattacharjee, Ashima; Dmitriev, Oleg Y et al. (2011) Cellular copper levels determine the phenotype of the Arg875 variant of ATP7B/Wilson disease protein. Proc Natl Acad Sci U S A 108:5390-5|
|Lutsenko, Svetlana (2010) Human copper homeostasis: a network of interconnected pathways. Curr Opin Chem Biol 14:211-7|
|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|
|LeShane, Erik S; Shinde, Ujwal; Walker, Joel M et al. (2010) Interactions between copper-binding sites determine the redox status and conformation of the regulatory N-terminal domain of ATP7B. J Biol Chem 285:6327-36|
|Gupta, Arnab; Lutsenko, Svetlana (2009) Human copper transporters: mechanism, role in human diseases and therapeutic potential. Future Med Chem 1:1125-1142|
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