Postdoc Michael Habeck receives Marie Curie fellowship
Postdoc Michael Habeck from Poul Nissen’s group has been awarded a 2 year Marie Curie fellowship from the European Commission, which will begin per 1 June 2018. The fellowship was awarded to conduct structural studies of Na,K-ATPase isoforms and mutants.
Isoform complexes of Na,K-ATPase, an αβ-heterooligomer, have recently been identified as crucial regulators of muscle and neural physiology and were furthermore identified as the primary cause of neurological diseases. Of particular interest are α2β2 & α2β3, which are expressed in muscle and astrocytes (α2β2) and the ciliary body (α2β3). Both exhibit a significantly lower affinity for K-ions and a steeper voltage dependence than the housekeeping α1β1 complex. These features keep α2-isoforms inactive at resting conditions but allow to respond to transient elevations of extracellular K after muscle and neuronal activity. Moreover, both complexes can be selectively inhibited by cardiac steroids, making them promising drug targets for the treatment of heart failure (α2β2) and glaucoma (α2β3). Differences in affinity for K and cardiac steroids were attributed to the β-subunit recently, yet the root cause and molecular details remained elusive. Hence, Michael Habeck would like to investigate the structure of α2-isoforms purified from the yeast Pichia pastoris by x-ray crystallography and cryo electron microscopy.
In addition to its physiological and pharmacological role, mutations of Na,K-ATPase cause severe neurological diseases, e.g. Alternating Hemiplegia of Childhood (AHC). Disease mutations typically inactivate the Na-pump causing severe motor and cognitive disorder. However, the effects of mutations on the ATPase’s reaction cycle have not been investigated in detail, leaving the cause of inactivation in the dark.
Part two of the proposal addresses this gap of knowledge. The two most common AHC mutations E815K and D801N will be expressed in P. pastoris and the effect of mutations on partial reactions of the Na,K-ATPase’s reaction cycle will be investigated and subsequently, structural studies will be carried out. This work will promote our understanding of Na,K-ATPase in health and disease and lay the foundation for the development of new drugs.
Movie of the Na,K-ATPase with ATP
All rights reserved. Use of the movie should refer to Nyblom et al. 2013.