title: Molecular basis of Wnt activation via the DIX domain protein Ccd1.
abstract: The Wnt signaling plays pivotal roles in embryogenesis and cancer, and the three DIX domain-containing proteins, Dvl, Axin, and Ccd1, play distinct roles in the initiation and regulation of canonical Wnt signaling. Overexpressed Dvl has a tendency to form large polymers in a cytoplasmic punctate pattern, whereas the biologically active Dvl in fact forms low molecular weight oligomers. The molecular basis for how the polymeric sizes of Dvl proteins are controlled upon Wnt signaling remains unclear. Here we show that Ccd1 up-regulates canonical Wnt signaling via acting synergistically with Dvl. We determined the crystal structures of wild type Ccd1-DIX and mutant Dvl1-DIX(Y17D), which pack into "head-to-tail" helical filaments. Structural analyses reveal two sites crucial for intra-filament homo- and hetero-interaction and a third site for inter-filament homo-assembly. Systematic mutagenesis studies identified critical residues from all three sites required for Dvl homo-oligomerization, puncta formation, and stimulation of Wnt signaling. Remarkably, Ccd1 forms a hetero-complex with Dvl through the "head" of Dvl-DIX and the "tail" of Ccd1-DIX, depolymerizes Dvl homo-assembly, and thereby controls the size of Dvl polymer. These data together suggest a molecular mechanism for Ccd1-mediated Wnt activation in that Ccd1 converts latent polymeric Dvl to a biologically active oligomer(s).
authors.affiliation: From the MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Yi-Tong
authors.initials: YT
authors.lastname: Liu
authors.affiliation: the Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Qiong-Jie
authors.initials: QJ
authors.lastname: Dan
authors.affiliation: From the MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Yingang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: From the MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liang
authors.affiliation: the MOE Key Laboratory of Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.affiliation: the MOE Key Laboratory of Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.affiliation: From the MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China,; the Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Wang
authors.affiliation: From the MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China,. Electronic address: jiaweiwu@mail.tsinghua.edu.cn.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Wu
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D051153:Wnt Proteins
chemical_list: C509983:Dixdc1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051153:Wnt Proteins