Structural mechanism of the Wnt-receptor interaction

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H01420
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Osaka University
• Principal Investigator: Takagi Junichi 大阪大学, 蛋白質研究所, 教授 (90212000)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: Wntシグナル / Ｘ線結晶構造解析 / 受容体 / 蛋白質間相互作用

Outline of Final Research Achievements

Wnt/beta-catenin signaling plays fundamental roles in organogenesis, tissue regeneration, and cancer, but current understanding of its molecular mechanism is limited due to the lack of high resolution structural information of mammalian Wnt proteins. Through this research project, we determined a 2.8 angstrome-resolution crystal structure of human Wnt3 in complex with its receptor Frizzled 8 for the first time. Furthermore, by using the RaPID system, we have performed in vitro selection against mouse Wnt3a to discover macrocyclic peptide binders, resulting in a peptide (WAp-D04) that can inhibit the receptor-mediated signaling processin cells. This work represents the first instance of molecules capable of inhibiting Wnt signaling through direct interaction with a Wnt protein, a molecular class for which targeting has been challenging due its highly hydrophobic nature.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

Wntシグナルは多細胞動物の発生・形態形成に必須なだけでなく、その異常はがんを含む様々な疾患に関わり、さらにはWntが組織幹細胞の生存と増殖に必須な増殖因子であることから再生医療を進めるためにも非常に重要な蛋白質である。本研究では、世界初のヒトWnt3の結晶構造解析により、これまで不明であったこの重要なシグナル伝達の分子メカニズムの原子レベルでの解明に大きく前進しただけで無く、がんに対する医薬のリードとなり得る化合物を得ることにも成功した。