Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization

doi:10.1101/gad.298331.117

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	Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization
	DeBruine, Zachary J.2; Ke, Jiyuan 5; Harikumar, Kaleeckal G.6; Gu, Xin 2; Borowsky, Peter 2; Williams, Bart O.1; Xu, Wenqing 4; Miller, Laurence J.6; Xu, H. Eric3,5 ; Melcher, Karsten 2
刊名	GENES & DEVELOPMENT
	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.
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关键词	FAMILIAL EXUDATIVE VITREORETINOPATHY ; STRUCTURAL BASIS ; BETA-CATENIN ; DIX DOMAIN ; PATHWAY ACTIVATION ; CRYSTAL-STRUCTURES ; PLASMA-MEMBRANE ; LRP6 ECTODOMAIN ; DEP DOMAIN ; RECEPTOR
WOS研究方向	Cell Biology ; Developmental Biology ; Genetics & Heredity
语种	英语
出版者	COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
WOS记录号	WOS:000402416700007
内容类型	期刊论文
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.