Challenge to elucidate the molecular mechanism of memory by single molecule imaging

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21122
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 28:Nano/micro science and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Shibata Mikihiro 金沢大学, ナノ生命科学研究所, 教授 (80631027)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: バイオイメージング / 原子間力顕微鏡 / 記憶・学習 / タンパク質 / 脳機能

Outline of Final Research Achievements

Decoding Ca2+ signaling in spine mediated by serine/threonine kinases including Ca2+/calmodulin-dependent kinase II (CaMKII) is crucial to synaptic plasticity that underlie learning and memory. CaMKII forms 12 subunits, all of which is a kinase that is activated by the binding of Ca2+/CaM. Despite the unique oligomer and importance in memory formation, the mechanism by which CaMKII integrates Ca2+ signals within its oligomer remains elusive. Here, we show flexibility of kinase domains in the CaMKII oligomer in basal state and activated state by directly visualizing nano-dynamics using HS-AFM. HS-AFM videos of CaMKII oligomer reveal that flexibility of kinase domains are changed dramatically depending on the binding of Ca2+/CaM and phosphorylated state, which causes both the autoinhibition and the positive cooperativity of phosphorylation. Our HS-AFM data provide a signal-integration mechanism in the CaMKII oligomer, which are fundamental to the molecular memory in brain.

Free Research Field

生物物理学

Academic Significance and Societal Importance of the Research Achievements

現代では、医療の大幅な発展により、ヒトの生物としての寿命が大幅に延びる一方、脳の機能障害による病気や精神疾患には、未だに有効な治療法が確立されていない。記憶を分子（タンパク質）レベルで明らかにし、その詳細な分子作動メカニズムを解明することは、人として幸福に人生を全うすることを助長し、人類の健康の増進に大きく寄与するに違いない。本研究は、記憶タンパク質ともいわれるCaMKIIの信号積算メカニズムの一端を高速AFMの１分子イメージングにより明らかにした。この研究成果は、脳内の神経細胞に形成される記憶をタンパク質１分子の構造変化やナノ動態で説明がつく可能性を示し、学術的意義が高いと考える。