Structural basis for Wnt signaling regulation by dynamic heterooligomer

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K07262
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Gunma University
• Principal Investigator: Terawaki Shin-ichi 群馬大学, 大学院理工学府, 助教 (10452533)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: Wntシグナル伝達 / 動的オリゴマー形成 / X線結晶解析 / 蛍光共鳴エネルギー移動

Outline of Final Research Achievements

Wnt signaling pathway plays an important role in determination for cell fate, such as embryonic development. The cytoplasmic signaling proteins, Axin, Coiled-coil-DIX1 (Ccd1), and Dvl form the platform for cytoplasmic signal transduction by making the dynamic oligomer through the homotypic and heterotypic interaction. In this study, we determined the crystal structure of Axin-Ccd1 heteroligomer forming the DIX domains conserved at both proteins. The structure of Axin-Ccd1 heterooligomer revealed the detail of the heterotypic interaction between the DIX domains and the rearrangement of the Axin homooligomer induced by the Ccd1-binding. The fluorescence resonance energy transfer measurement and mutation study indicated that Ccd1 induces the rearrangement of Axin homooligmer in solution by the heterotypic interaction. These findings suggest the requirement investigating the relationship between the rearrangement of Axin homooligomer and the regulatory mechanism for Wnt signaling.

Free Research Field

構造生物化学

Academic Significance and Societal Importance of the Research Achievements

Wntシグナル伝達経路は、構成するタンパク質の機能異常が、細胞のがん化や精神性疾患、糖尿病、骨・軟骨性疾患に関係することが臨床研究から報告されているため、本研究の成果は、創薬に応用することができる。動的オリゴマー形成を介するシグナル伝達制御は、Wnt経路に特異的な分子機構であるため、その制御の仕組みを理解することで、がんや精神性疾患などに対する副作用の少ない薬剤開発が可能になることが期待できる。