This project focuses on the investigation of disease mutants of Na,K-ATPase. The Na,K-ATPase is a protein found in the cell membrane of virtually every animal cell that maintains the unequal distribution of sodium and potassium between the inside and outside of cells. It is thus vital for numerous functions such as import of other solute, e.g. sugars, neurotransmitters and other ions, cell volume regulation as well as maintaining the electric excitability of neurons and muscle. Mutations of single amino acids have recently been identified as the cause of several neurological diseases. These include Alternating hemiplegia of childhood (AHC), which is characterized by an early onset in infancy, motor impairments such as hemiplegia, i.e. episodic weakness of one half of the body, epileptic seizures and developmental delay. Since there are more than 200 individual mutations causing the disease symptoms vary from milder outcomes to early death. The disease does not only affect individuals, yet depending on severity also their family and caretakers. On of the most severe mutations causing AHC is the E815K mutant, a change of a negatively charged glutamate to a positively charged lysine, which accounts for more than 10% of cases. We aim at studying this mutant and its affect on pump function and the impact on the structure of the protein. We hope that a better understanding of mutations such as E815K will help to pave the way towards cures and that structural insights will lead to drug developments in the near future.
We aimed at studying the underlying kinetic mechanism of the E815K-mutation and characterize its impact on the structure of the protein.
