Direct interaction of beta-amyloid with Na,K-ATPase as a putative regulator of the enzyme function.
By maintaining the Na(+) and K(+) transmembrane gradient mammalian Na,K-ATPase acts as a key regulator of neuronal electrotonic properties. Na,K-ATPase has an important role in synaptic transmission and memory formation. Accumulation of beta-amyloid (Aβ) at the early stages of Alzheimer's disease is accompanied by reduction of Na,K-ATPase functional activity. The molecular mechanism behind this phenomenon is not known. Here we show that the monomeric Aβ(1-42) forms a tight (Kd of 3 μM), enthalpy-driven equimolar complex with α1β1 Na,K-ATPase. The complex formation results in dose-dependent inhibition of the enzyme hydrolytic activity. The binding site of Aβ(1-42) is localized in the "gap" between the alpha- and beta-subunits of Na,K-ATPase, disrupting the enzyme functionality by preventing the subunits from shifting towards each other. Interaction of Na,K-ATPase with exogenous Aβ(1-42) leads to a pronounced decrease of the enzyme transport and hydrolytic activity and Src-kinase activation in neuroblastoma cells SH-SY5Y. This interaction allows regulation of Na,K-ATPase activity by short-term increase of the Aβ(1-42) level. However prolonged increase of Aβ(1-42) level under pathological conditions could lead to chronical inhibition of Na,K-ATPase and disruption of neuronal function. Taken together, our data suggest the role of beta-amyloid as a novel physiological regulator of Na,K-ATPase.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Irina Yu
IY
Petrushanko
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Vladimir A
VA
Mitkevich
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Anastasia A
AA
Anashkina
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Alexei A
AA
Adzhubei
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Ksenia M
KM
Burnysheva
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Valentina A
VA
Lakunina
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Yulia V
YV
Kamanina
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Elena A
EA
Dergousova
Faculty of Biology, M.V. Lomonosov Moscow State University, 119234 Moscow, Russia.
Olga D
OD
Lopina
Institute of Veterinary Physiology, Vetsuisse Faculty, and the Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, CH-8057 Zurich, Switzerland.
Omolara O
OO
Ogunshola
Institute of Veterinary Physiology, Vetsuisse Faculty, and the Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, CH-8057 Zurich, Switzerland.
Anna Yu
AY
Bogdanova
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov St. 32, 119991 Moscow, Russia.
Alexander A
AA
Makarov
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation; D019793:Fluorescein / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000378:metabolism*; D012996:Solutions; D019061:src-Family Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions; C075222:amyloid beta-protein (1-42); D019061:src-Family Kinases; D000254:Sodium-Potassium-Exchanging ATPase; D019793:Fluorescein