The SFB 1078 kindly invites you to the following colloquium talk:

Prof. Ronald Clarke hosted by Joachim Heberle (FUB):

Title: Hidden Secrets of Ion Pump Function

The Na⁺,K⁺-pump (or Na⁺,K⁺-ATPase) is one of the most important energy-transforming systems of animal physiology. It utilises the free energy of adenosine triphosphate (ATP) hydrolysis to do the electrical work of pumping Na⁺ and K⁺ ions against their electrochemical potential gradients across the plasma membrane of all living animal cells. In this way the chemical energy of ATP is transformed into a non-equilibrium Na⁺ concentration gradient across the membrane as a store of energy [1]. For the discovery of the Na⁺,K⁺-pump [2], Jens Christian Skou of the University of Aarhus, Denmark, received the 1997 Nobel Prize in Chemistry. The energy stored in the Na⁺ gradient is utilised as an energy source to drive numerous vital physiological processes. These include nerve impulse propagation, muscle contraction, and nutrient reabsorption in the kidney.

The Na⁺,K⁺-pump is an integral membrane protein. Since 2007 several crystal structures of the protein have been determined by X-ray crystallography and cryo-electron-microscopy [3]. However, none of the published structural studies have been able to resolve the protein’s intrinsically disordered N-terminus, and hence the structures have provided no information on the role that this region of the enzyme plays in the ion pumping mechanism. Information from biophysical and bioinformatic analyses is mounting [4], however, that the N-terminus is involved in a crucial lipid-protein interaction, whereby positively charged lysine residues of the N-terminus interact electrostatically with the lipid head-groups of negatively charged phosphatidylserine (PS) molecules on the cytoplasmic face of the plasma membrane. PS is concentrated in the cytoplasmic leaflet of the plasma membrane of all animal cells via a phospholipid flippase embedded in the membrane, which also uses the energy derived from ATP hydrolysis to maintain transverse lipid asymmetry across the plasma membrane. The electrostatic interaction between the N-terminus and the membrane provides an ideal regulatory mechanism for the Na⁺,K⁺-pump. A decrease in charge of the N-terminus by the phosphorylation of conserved serine and tyrosine residues allows for an “electrostatic switch” mechanism, whereby the N-terminus is released from the membrane, altering the overall conformation of the protein, and modulating its ion pumping activity.

[1] R. J. Clarke and X. Fan, Clin. Exp. Pharmacol. Physiol. 2011, 38, 726.
[2] J. C. Skou, Biochim. Biophys. Acta 1957, 23, 394.
[3] J. P. Morth et al, Nature 2007, 450, 1043.
[4] E.-L. Blayney et al, Int. J. Mol. Sci. 2023, 24, 67.