The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization.
The Wnt signaling pathway controls numerous cell fates in animal development and is also a major cancer pathway. Dishevelled (Dvl) transduces the Wnt signal by interacting with the cytoplasmic Axin complex. Dvl and Axin each contain a DIX domain whose molecular properties and structure are unknown. Here, we demonstrate that the DIX domain of Dvl2 mediates dynamic polymerization, which is essential for the signaling activity of Dvl2. The purified domain polymerizes gradually, reversibly and in a concentration dependent manner, ultimately forming fibrils. The Axin DIX domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal. The DIX domain thus seems to mediate the formation of a dynamic interaction platform with a high local concentration of binding sites for transient Wnt signaling partners; this represents a previously uncharacterized mechanistic principle, signaling by reversible polymerization.
Schwarz-Romond
Thomas
T
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Fiedler
Marc
M
Shibata
Naoki
N
Butler
P Jonathan G
PJ
Kikuchi
Akira
A
Higuchi
Yoshiki
Y
Bienz
Mariann
M
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D060466:Axin Protein; D001483:Base Sequence; D003460:Crystallization; D000072261:Dishevelled Proteins; D006801:Humans; D047468:Immunoprecipitation; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology*; D014461:Ultracentrifugation; D051153:Wnt Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D011108:Polymers; D012097:Repressor Proteins; D051153:Wnt Proteins