Wnt是脂修飾的成形素,，主要通過Frizzled受體在機體發(fā)育中發(fā)揮重要作用,。5月31日Science雜志在線發(fā)表了Claudia Y. Janda等的研究論文,，揭示了Frizzled識別Wnt的結構生物學機制,。
研究者以3.25 埃米的分辨率,，解析了非洲爪蟾Wnt8(XWnt8)與小鼠Frizzled-8富含半胱氨酸結構域（Fz8-CRD）復合體的結構,。他們發(fā)現(xiàn)一種不同尋常的Wnt二結構域結構,。該機構與已知的蛋白折疊似乎都不同：它像一只手一樣,，用拇指和食指在兩個不同的結合位點上握住Fz8-CRD。其中一個位點被從Wnt分子大拇指結構尖端187位絲氨酸所伸出的棕櫚油酸脂基團所占據(jù),。在另一個結合位點上,，保守的Wnt食指結構尖端含有的疏水氨基酸與Fz8-CRD結構域反面的凹陷相接觸。在這兩個界面的氨基酸保守性似乎促進了配體和受體間的交叉反應,。
這項研究,，對于理解Wnt的多功能性，并據(jù)此設計抗腫瘤和再生醫(yī)學藥物都有重要意義,。(生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
Structural Basis of Wnt Recognition by Frizzled
Claudia Y. Janda,Deepa Waghray,Aron M. Levin,et al
Wnts are lipid-modified morphogens that play critical roles in development principally through engagement of Frizzled receptors. The 3.25 A structure of Xenopus Wnt8 (XWnt8) in complex with mouse Frizzled-8 cysteine-rich domain (CRD) reveals an unusual two-domain Wnt structure, not obviously related to known protein folds, resembling a “hand” with “thumb” and “index” fingers extended to grasp the Fz8-CRD at two distinct binding sites. One site is dominated by a palmitoleic acid lipid group projecting from Serine 187 at the tip of Wnt’s thumb into a deep groove in the Fz8-CRD. In the second binding site, the conserved tip of Wnt’s "index finger" forms hydrophobic amino acid contacts with a depression on the opposite side of the Fz8-CRD. The conservation of amino acids in both interfaces appears to facilitate ligand-receptor cross-reactivity, which has important implications for understanding Wnt’s functional pleiotropy and for developing Wnt-based drugs for cancer and regenerative medicine.
