Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex
文献类型：期刊论文
| 作者 | Ke, Jiyuan2; Harikumar, Kaleeckal G.3; Erice, Clara2; Chen, Chen2; Gu, Xin2; Wang, Liren2; Parker, Naomi2; Cheng, Zhihong4; Xu, Wenqing4; Williams, Bart O.1,5 |
| 刊名 | GENES & DEVELOPMENT
 |
| 出版日期 | 2013-11-01 |
| 卷号 | 27期号:21页码:2305-2319 |
| 关键词 | Norrin structure cystine knot growth factor Wnt/beta-catenin signaling Frizzled 4 low-density lipoprotein receptor-related protein 5/6 tetraspanin 12 |
| ISSN号 | 0890-9369 |
| DOI | 10.1101/gad.228544.113 |
| 文献子类 | Article |
| 英文摘要 | Norrin is a cysteine-rich growth factor that is required for angiogenesis in the eye, ear, brain, and female reproductive organs. It functions as an atypical Wnt ligand by specifically binding to the Frizzled 4 (Fz4) receptor. Here we report the crystal structure of Norrin, which reveals a unique dimeric structure with each monomer adopting a conserved cystine knot fold. Functional studies demonstrate that the novel Norrin dimer interface is required for Fz4 activation. Furthermore, we demonstrate that Norrin contains separate binding sites for Fz4 and for the Wnt ligand coreceptor Lrp5 (low-density lipoprotein-related protein 5) or Lrp6. Instead of inducing Fz4 dimerization, Norrin induces the formation of a ternary complex with Fz4 and Lrp5/6 by binding to their respective extracellular domains. These results provide crucial insights into the assembly and activation of the Norrin-Fz4-Lrp5/6 signaling complex. |
| WOS关键词 | RETINAL VASCULAR DEVELOPMENT ; COUPLED SECRETIN RECEPTOR ; WNT SIGNALING PATHWAY ; MOLECULAR RECOGNITION ; GROWTH-FACTORS ; PROTEIN ; DISEASE ; OLIGOMERIZATION ; VITREORETINOPATHY ; DOMAIN |
| 资助项目 | National Institute of Health[DK71662] ; National Institute of Health[DK46577] |
| WOS研究方向 | Cell Biology ; Developmental Biology ; Genetics & Heredity |
| 语种 | 英语 |
| WOS记录号 | WOS:000326921900003 |
| 出版者 | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277396]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Xu, H. Eric |
| 作者单位 | 1.Van Andel Res Inst, Lab Cell Signaling & Carcinogenesis, Grand Rapids, MI 49503 USA; 2.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 3.Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Scottsdale, AZ 85259 USA; 4.Univ Washington, Sch Med, Dept Biol Struct, Seattle, WA 98195 USA; 5.Van Andel Res Inst, Ctr Skeletal Dis Res, Grand Rapids, MI 49503 USA; 6.Van Andel Res Inst, Lab Struct Biol & Biochem, Grand Rapids, MI 49503 USA; 7.Chinese Acad Sci, Van Andel Res Inst, Shanghai Inst Mat Med Ctr, Key Lab Receptor Res,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ke, Jiyuan,Harikumar, Kaleeckal G.,Erice, Clara,et al. Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex[J]. GENES & DEVELOPMENT,2013,27(21):2305-2319. |
| APA | Ke, Jiyuan.,Harikumar, Kaleeckal G..,Erice, Clara.,Chen, Chen.,Gu, Xin.,...&Xu, H. Eric.(2013).Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex.GENES & DEVELOPMENT,27(21),2305-2319. |
| MLA | Ke, Jiyuan,et al."Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex".GENES & DEVELOPMENT 27.21(2013):2305-2319. |
入库方式： OAI收割
来源：上海药物研究所
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