Familial hemiplegic migraine mutations affect Na,K-ATPase domain interactions

Biochim Biophys Acta. 2013 Dec;1832(12):2173-9. doi: 10.1016/j.bbadis.2013.08.003. Epub 2013 Aug 15.

Abstract

Familial hemiplegic migraine (FHM) is a monogenic variant of migraine with aura. One of the three known causative genes, ATP1A2, which encodes the α2 isoform of Na,K-ATPase, causes FHM type 2 (FHM2). Over 50 FHM2 mutations have been reported, but most have not been characterized functionally. Here we study the molecular mechanism of Na,K-ATPase α2 missense mutations. Mutants E700K and P786L inactivate or strongly reduce enzyme activity. Glutamic acid 700 is located in the phosphorylation (P) domain and the mutation most likely disrupts the salt bridge with Lysine 35, thereby destabilizing the interaction with the actuator (A) domain. Mutants G900R and E902K are present in the extracellular loop at the interface of the α and β subunit. Both mutants likely hamper the interaction between these subunits and thereby decrease enzyme activity. Mutants E174K, R548C and R548H reduce the Na(+) and increase the K(+) affinity. Glutamic acid 174 is present in the A domain and might form a salt bridge with Lysine 432 in the nucleotide binding (N) domain, whereas Arginine 548, which is located in the N domain, forms a salt bridge with Glutamine 219 in the A domain. In the catalytic cycle, the interactions of the A and N domains affect the K(+) and Na(+) affinities, as observed with these mutants. Functional consequences were not observed for ATP1A2 mutations found in two sporadic hemiplegic migraine cases (Y9N and R879Q) and in migraine without aura (R51H and C702Y).

Keywords: ATP1A2; Domain interaction; FHM2; Familial hemiplegic migraine; Na,K-ATPase; α2 isoform.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Humans
  • Migraine with Aura / genetics*
  • Migraine with Aura / metabolism
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation, Missense / genetics*
  • Ouabain / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Sodium-Potassium-Exchanging ATPase / chemistry
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Sodium-Potassium-Exchanging ATPase / metabolism*

Substances

  • Ouabain
  • ATP1A2 protein, human
  • Sodium-Potassium-Exchanging ATPase