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Mads Schak Toustrup-Jensen

Mutations Phe785Leu and Thr618Met in Na+, K+-ATPase, Associated with Familial Rapid-Onset Dystonia Parkinsonism, Interfere with Na+ Interaction by Distinct Mechanisms

Publikation: KonferencebidragPosterForskning

  • Afdeling for Fysiologi

The Na+, K+-ATPase plays key roles in brain function. Recently, missense mutations in the Na+, K+-ATPase were found associated with familial rapid-onset dystonia parkinsonism (FRDP). Here, we have characterized the functional consequences of FRDP mutations Phe785Leu and Thr618Met. Both mutations lead to functionally altered, but active, Na+, K+-pumps that display reduced apparent affinity for cytoplasmic Na+, but the underlying mechanism differs between the mutants. In Phe785Leu, the interaction of the E1 form with Na+ is defective, and the E1-E2 equilibrium is not displaced. In Thr618Met, the Na+ affinity is reduced because of displacement of the conformational equilibrium in favor of the K+-occluded E2(K2) form. In both mutants, K+ interaction at the external activating sites of the E2P phosphoenzyme is normal. The change of cellular Na+ homeostasis is likely a major factor contributing to the development of FRDP in patients carrying the Phe785Leu or Thr618Met mutation. Phe785Leu moreover interferes with Na+ interaction on the extracellular side and reduces the affinity for ouabain significantly. Analysis of two additional Phe785 mutants, Phe785Leu/Leu786Phe and Phe785Tyr, demonstrated that the aromatic function of the side chain, as well as its exact position, is critical for Na+ and ouabain binding. Structural modeling demonstrates that substitution of Phe785 disturbs its participation in a hydrophobic network between three transmembrane segments. It also indicates that the Thr618Met mutation interferes with the bonding pattern in the catalytic site in the E1 form, thereby destabilizing E1 relative to E2(K2).


StatusUdgivet - 2007
BegivenhedPhD day 2007, Faculty of Health Sciences, University of Aarhus - Århus, Danmark
Varighed: 12 jan. 200712 jan. 2007


KonferencePhD day 2007, Faculty of Health Sciences, University of Aarhus

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