PUBLICATION
Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain
- Authors
- Terawaki, S.I., Fujita, S., Katsutani, T., Shiomi, K., Keino-Masu, K., Masu, M., Wakamatsu, K., Shibata, N., Higuchi, Y.
- ID
- ZDB-PUB-170812-5
- Date
- 2017
- Source
- Scientific Reports 7: 7739 (Journal)
- Registered Authors
- Shiomi, Kensuke
- Keywords
- Morphogen signalling, X-ray crystallography
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Binding Sites
- Intracellular Signaling Peptides and Proteins/chemistry*
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism*
- Mice
- Models, Molecular
- Mutation
- Protein Binding
- Protein Conformation
- Protein Interaction Domains and Motifs*
- Protein Multimerization*
- Structure-Activity Relationship
- Wnt Signaling Pathway*
- Zebrafish
- PubMed
- 28798413 Full text @ Sci. Rep.
Citation
Terawaki, S.I., Fujita, S., Katsutani, T., Shiomi, K., Keino-Masu, K., Masu, M., Wakamatsu, K., Shibata, N., Higuchi, Y. (2017) Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain. Scientific Reports. 7:7739.
Abstract
Wnt signaling plays an important role in governing cell fate decisions. Coiled-coil-DIX1 (Ccd1), Dishevelled (Dvl), and Axin are signaling proteins that regulate the canonical pathway by controlling the stability of a key signal transducer β-catenin. These proteins contain the DIX domain with a ubiquitin-like fold, which mediates their interaction in the β-catenin destruction complex through dynamic head-to-tail polymerization. Despite high sequence similarities, mammalian Ccd1 shows weaker stimulation of β-catenin transcriptional activity compared with zebrafish (z) Ccd1 in cultured cells. Here, we show that the mouse (m) Ccd1 DIX domain displays weaker ability for homopolymerization than that of zCcd1. Furthermore, X-ray crystallographic analysis of mCcd1 and zCcd1 DIX domains revealed that mCcd1 was assembled into a double-helical filament by the insertion of the β1-β2 loop into the head-to-tail interface, whereas zCcd1 formed a typical single-helical polymer similar to Dvl1 and Axin. The mutation in the contact interface of mCcd1 double-helical polymer changed the hydrodynamic properties of mCcd1 so that it acquired the ability to induce Wnt-specific transcriptional activity similar to zCcd1. These findings suggest a novel regulatory mechanism by which mCcd1 modulates Wnt signaling through auto-inhibition of dynamic head-to-tail homopolymerization.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping