Abnormal allostery in ER calcium channel involved in neurodegenerative disease

2022 Fiscal Year Final Research Report

• Project/Area Number: 15K06791
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Toho University (2019-2022); Kindai University (2018); Institute of Physical and Chemical Research (2015-2017)
• Principal Investigator: Hamada Kozo 東邦大学, 理学部, 訪問研究員 (00311358)
• Project Period (FY): 2015-04-01 – 2023-03-31
• Keywords: allostery / calcium signaling / ion channel / second messenger / x-ray crystallography / endoplasmic reticulum / autophagy / dementia

Outline of Final Research Achievements

Dementia is an international issue in an aging society with a declining birthrate, but its onset mechanism is still not fully understood, and it is necessary to search for new molecular mechanisms. In this study, we will explore the molecular mechanisms underlying dementia by focusing on intracellular calcium channels present in the endoplasmic reticulum. The IP3 receptor present on the membrane of the endoplasmic reticulum consists of four subunits and functions as a calcium channel. This calcium channel is essential for brain function and is known to play a role in memory and learning. In this research project, for the first time in the world, we succeeded in X-ray crystal structure analysis of a huge IP3 receptor cytoplasmic domain consisting of 2217 amino acid residues, and published an original paper during the project period (PNAS, 2017).

Free Research Field

biochemistry

Academic Significance and Societal Importance of the Research Achievements

この研究成果は日刊工業新聞、科学新聞、化学工業日報に掲載され、二つの異なる国際会議で発表を認められました（GRC, 2017; GRC, 2018）。Ｘ線結晶構造解析によって示唆された「リーフレット」部位の変異体を作成し、IP3が結合して生じる構造変化がチャネルに伝達されるメカニズムを証明しました。これらの成果と最近知見をまとめ総説論文を出版しました（Annual Rev Physiol, 2020）。この成果は認知症の原因となるアポトーシスや細胞老化に関わると考えられ、国際共同研究を進め原著論文を発表しました(BBA, 2022, Cell Death Diff, 2022)。