Structural basis of propagation ability and toxicity of amyloid fibrils as elucidated through the analysis of prefibrillar intermediates

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H04778
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biophysics
• Research Institution: Kobe University
• Principal Investigator: CHATANI Eri 神戸大学, 理学研究科, 准教授 (00432493)
• Co-Investigator(Kenkyū-buntansha): 山本 直樹 神戸大学, 理学研究科, 特命助教 (90580671)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 蛋白質 / ミスフォールディング / アミロイド / 中間体 / 伝播

Outline of Final Research Achievements

Amyloid fibrils typically propagate their own structures by a template-dependent growth mechanism, in which the termini of the fibrils serve as a propagation template. To elucidate the property of the template structure and the mechanism of its formation, we focused on “prefibrillar intermediates”, i.e., early aggregates that are assumed to be formed before demonstrating the propagation ability. We have identified a characteristic pathway of the formation of amyloid fibrils of human insulin B chain, in which prefibrillar intermediates populated significantly. We have analyzed the structural properties of the prefibrillar intermediates and tracked their formation in a time-dependent manner. We have also found the inhibition of the B-chain amyloid formation by fibrinogen, which interacted with the prefibrillar intermediates.

Free Research Field

生物学

Academic Significance and Societal Importance of the Research Achievements

アミロイド線維のもつ伝播性は、アミロイドーシスの発症・進行を担う性質として注目されている。線維前駆中間体に着眼した本研究は、伝播性を獲得し増殖するまでのタンパク質の会合や構造形成の実態に迫ろうとするものであり、タンパク質科学における学術的意義だけでなく早期診断および治療にも貢献することができる。特に鋳型や線維前駆中間体は、線維の形成阻害や分解促進のターゲットとして有用である可能性が高く、戦略的な治療と予防法の開発につながることが期待される。