Wnt是脂修饰的成形素，主要通过Frizzled受体在机体发育中发挥重要作用。5月31日Science杂志在线发表了Claudia Y. Janda等的研究论文，揭示了Frizzled识别Wnt的结构生物学机制。
研究者以3.25 埃米的分辨率，解析了非洲爪蟾Wnt8(XWnt8)与小鼠Frizzled-8富含半胱氨酸结构域（Fz8-CRD）复合体的结构。他们发现一种不同寻常的Wnt二结构域结构。该机构与已知的蛋白折叠似乎都不同：它像一只手一样，用拇指和食指在两个不同的结合位点上握住Fz8-CRD。其中一个位点被从Wnt分子大拇指结构尖端187位丝氨酸所伸出的棕榈油酸脂基团所占据。在另一个结合位点上，保守的Wnt食指结构尖端含有的疏水氨基酸与Fz8-CRD结构域反面的凹陷相接触。在这两个界面的氨基酸保守性似乎促进了配体和受体间的交叉反应。
这项研究，对于理解Wnt的多功能性，并据此设计抗肿瘤和再生医学药物都有重要意义。(生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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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.
