Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization
文献类型：期刊论文
| 作者 | DeBruine, Zachary J.2; Ke, Jiyuan5; Harikumar, Kaleeckal G.6; Gu, Xin2; Borowsky, Peter2; Williams, Bart O.1; Xu, Wenqing4; Miller, Laurence J.6; Xu, H. Eric3,5 ; Melcher, Karsten2
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| 刊名 | GENES & DEVELOPMENT
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| 出版日期 | 2017-05-01 |
| 卷号 | 31期号:9页码:916-926 |
| 关键词 | Wnt Frizzled signalosome cysteine-rich domain WNT5A Frizzled-4 |
| ISSN号 | 0890-9369 |
| DOI | 10.1101/gad.298331.117 |
| 文献子类 | Article |
| 英文摘要 | Wnt/beta-catenin signaling is activated when extracellular Wnt ligands bind Frizzled (FZD) receptors at the cell membrane. Wnts bind FZD cysteine-rich domains (CRDs) with high affinity through a palmitoylated N-terminal "thumb" and a disulfide-stabilized C-terminal "index finger," yet how these binding events trigger receptor activation and intracellular signaling remains unclear. Here we report the crystal structure of the Frizzled-4 (FZD4) CRD in complex with palmitoleic acid, which reveals a CRD tetramer consisting of two cross-braced CRD dimers. Each dimer is stabilized by interactions of one hydrophobic palmitoleic acid tail with two CRD palmitoleoyl-binding grooves oriented end to end, suggesting that the Wnt palmitoleoyl group stimulates CRD-CRD interaction. Using bioluminescence resonance energy transfer (BRET) in live cells, we show that WNT5A stimulates dimerization of membrane-anchored FZD4 CRDs and oligomerization of full-length FZD4, which requires the integrity of CRD palmitoleoyl-binding residues. These results suggest that FZD receptors may form signalosomes in response to Wnt binding through the CRDs and that the Wnt palmitoleoyl group is important in promoting these interactions. These results complement our understanding of lipoprotein receptor-related proteins 5 and 6 (LRP5/6), Dishevelled, and Axin signalosome assembly and provide a more complete model for Wnt signalosome assembly both intracellularly and at the membrane. |
| WOS关键词 | FAMILIAL EXUDATIVE VITREORETINOPATHY ; STRUCTURAL BASIS ; BETA-CATENIN ; DIX DOMAIN ; PATHWAY ACTIVATION ; CRYSTAL-STRUCTURES ; PLASMA-MEMBRANE ; LRP6 ECTODOMAIN ; DEP DOMAIN ; RECEPTOR |
| 资助项目 | Michigan Economic Development Corporation[00000000] ; Michigan Technology Tri-Corridor[085P1000817] ; Office of Science of the US Department of Energy[DE-AC02-06CH11357] |
| WOS研究方向 | Cell Biology ; Developmental Biology ; Genetics & Heredity |
| 语种 | 英语 |
| WOS记录号 | WOS:000402416700007 |
| 出版者 | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272683]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Xu, H. Eric; Melcher, Karsten |
| 作者单位 | 1.Van Andel Res Inst, Lab Cell Signaling & Carcinogenesis, Ctr Skeletal Dis Res, Grand Rapids, MI 49503 USA; 2.Van Andel Res Inst, Lab Struct Biol & Biochem, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Van Andel Res Inst,Shanghai Inst Mat Med Ctr, Shanghai 201203, Peoples R China 4.Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA; 5.Van Andel Res Inst, Lab Struct Sci, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA; 6.Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Scottsdale, AZ 85259 USA; |
| 推荐引用方式 GB/T 7714 | DeBruine, Zachary J.,Ke, Jiyuan,Harikumar, Kaleeckal G.,et al. Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization[J]. GENES & DEVELOPMENT,2017,31(9):916-926. |
| APA | DeBruine, Zachary J..,Ke, Jiyuan.,Harikumar, Kaleeckal G..,Gu, Xin.,Borowsky, Peter.,...&Melcher, Karsten.(2017).Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization.GENES & DEVELOPMENT,31(9),916-926. |
| MLA | DeBruine, Zachary J.,et al."Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization".GENES & DEVELOPMENT 31.9(2017):916-926. |
入库方式： OAI收割
来源：上海药物研究所
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