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

Autor: Herman G.P. Swarts, Karl M. Weigand, Hanka Venselaar, Frans G. M. Russel, Jan B. Koenderink, Arn M. J. M. van den Maagdenberg
Rok vydání: 2013
Předmět:
Models
Molecular
Chemical and physical biology [NCMLS 7]
α2 isoform
Energy and redox metabolism [NCMLS 4]
Genetics and epigenetic pathways of disease [NCMLS 6]
alpha 2 isoform
Protein Conformation
Blotting
Western
Migraine with Aura
Mutant
Mutation
Missense
Membrane transport and intracellular motility [NCMLS 5]
medicine.disease_cause
ATP1A2
medicine
Humans
Missense mutation
Na
Na+/K+-ATPase
Domain interaction
Ouabain
Molecular Biology
Familial hemiplegic migraine
Mutation
FHM2
Chemistry
Glutamic acid
medicine.disease
Protein Structure
Tertiary
Membrane transport and intracellular motility Renal disorder [NCMLS 5]
Biochemistry
K-ATPase
Na
K-ATPase
Mutagenesis
Site-Directed
Molecular Medicine
Salt bridge
Sodium-Potassium-Exchanging ATPase
Protein Binding
Membrane transport and intracellular motility Poverty-related infectious diseases [NCMLS 5]
Zdroj: BBA-Molecular Basis of Disease, 1832(12), 2173-2179
Biochimica et Biophysica Acta. Molecular Basis of Disease, 1832, 2173-9
Biochimica et Biophysica Acta. Molecular Basis of Disease, 1832, 12, pp. 2173-9
ISSN: 0925-4439
DOI: 10.1016/j.bbadis.2013.08.003
Popis: Contains fulltext : 125451.pdf (Publisher’s version ) (Closed access) Familial hemiplegic migraine (FHM) is a monogenic variant of migraine with aura. One of the three known causative genes, ATP1A2, which encodes the alpha2 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 alpha2 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 alpha and beta 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).
Databáze: OpenAIRE
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