Na+,K+-ATPase (Na+-pump) transports three Na+ from cytoplasm to external and two K+ oppositely with one ATP hydrolyzed. Gradients of these ion concentrations are used for various fundamental activities like electric potential, driving force for secondary transporters and regulation of osmotic pressure. Aggregates of a-synuclein and b-amyloid target Na+-pump and these binding have been reported to stop the enzymatic activity of Na+-pump in neurodegeneration. It is a very interesting question how these aggregates inhibit Na+-pump activity because their binding region doesn’t have any structural changes in the reaction cycle. One potential answer is that Na+-pump may actively tilt its overall structure against membrane dependently on its intermediate states of the reaction cycle and, a-synuclein and b-amyloid aggregates may stop such “rocking motion” of Na+-pump. In this study, to validate these possibilities, I showed tilting motion of Na+-pump in two intermediate states, E1·3Na+ and E2P, by visualizing membrane in crystal structure of Na+-pump and Na+-pump-reconstituted nanodisc. Such tilting motion of Na+-pump clearly takes place in its reaction cycle and a maximum tilting was estimated ~10˚ between E1∙3Na+ and E1~P·ADP·3Na+ and a structural movement of the binding region for a-synuclein and b-amyloid was estimated about ~10 Å. a-synuclein or b-amyloid binding to Na+-pump probably inhibit tilting of Na+-pump to membrane.はじめにInstitute for Quantitative Biosciences, Laboratory of Membrane ProteinsAbstractNa+,K+-ATPase (Na+ポンプ)は全ての動物細胞の形質膜に存在し，ATP 1分子あたり3個のNa+を細胞外へ，2個のK+を細胞内へ濃度勾配に逆らって輸送するイオンポンプである（図1）．こうして形成されるイオン濃度差のエネルギーは神経の電気信号，浸透圧調節，物質輸送などに用いられ，東京大学定量生命科学研究所膜蛋白質解析研究分野The University of Tokyo,― 108 ―Structural basis for drug development targeting Na+-pump ナトリウムポンプを標的とした，神経変性疾患のための薬剤開発の構造的基盤for neurodegenerative diseases金井 隆太Ryuta Kanai
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