Structural Basis of Wnt Recognition by Frizzled

被引：747

作者：

Janda, Claudia Y. ^{[1
,2
,3
]}

Waghray, Deepa ^{[1
,2
,3
]}

Levin, Aron M. ^{[1
,2
,3
]}

Thomas, Christoph ^{[1
,2
,3
]}

Garcia, K. Christopher ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA

来源：

SCIENCE | 2012年 / 337卷 / 6090期

关键词：

SIGNALING INHIBITION; CATENIN PATHWAY; PROTEINS; RECEPTORS; ACTIVATE; BINDING; FAMILY; CANCER; DOMAIN; LRP6;

D O I：

10.1126/science.1222879

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Wnts are lipid-modified morphogens that play critical roles in development principally through engagement of Frizzled receptors. The 3.25 angstrom structure of Xenopus Wnt8 (XWnt8) in complex with mouse Frizzled-8 (Fz8) 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.

引用

页码：59 / 64

页数：6

共 43 条

[1]

Structural Basis of Wnt Signaling Inhibition by Dickkopf Binding to LRP5/6 [J].