Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain
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 wi...
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| Format: | Article |
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Nature Portfolio
2017-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-08019-5 |
| _version_ | 1818425406858985472 |
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| author | Shin-ichi Terawaki Shohei Fujita Takuya Katsutani Kensuke Shiomi Kazuko Keino-Masu Masayuki Masu Kaori Wakamatsu Naoki Shibata Yoshiki Higuchi |
| author_facet | Shin-ichi Terawaki Shohei Fujita Takuya Katsutani Kensuke Shiomi Kazuko Keino-Masu Masayuki Masu Kaori Wakamatsu Naoki Shibata Yoshiki Higuchi |
| author_sort | Shin-ichi Terawaki |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T14:13:26Z |
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| id | doaj.art-82ea2c14f6a04fdfac2aa1e522bd3b63 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T14:13:26Z |
| publishDate | 2017-08-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-82ea2c14f6a04fdfac2aa1e522bd3b632022-12-21T22:58:15ZengNature PortfolioScientific Reports2045-23222017-08-017111310.1038/s41598-017-08019-5Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domainShin-ichi Terawaki0Shohei Fujita1Takuya Katsutani2Kensuke Shiomi3Kazuko Keino-Masu4Masayuki Masu5Kaori Wakamatsu6Naoki Shibata7Yoshiki Higuchi8Graduate School of Science and Technology, Gunma University, 1-5-1 Tenjin-cho, KiryuGraduate School of Science and Technology, Gunma University, 1-5-1 Tenjin-cho, KiryuDepartment of Life Science and Department of Picobiology, Graduate School of Life Science, University of Hyogo, 3-2-1 Koto, Kamigori-cho, Ako-gunDepartment of Molecular Neurobiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, TsukubaDepartment of Molecular Neurobiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, TsukubaDepartment of Molecular Neurobiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, TsukubaGraduate School of Science and Technology, Gunma University, 1-5-1 Tenjin-cho, KiryuRIKEN SPring-8 Center, 1-1-1 Koto, Mikazuki-cho, Sayo-gunRIKEN SPring-8 Center, 1-1-1 Koto, Mikazuki-cho, Sayo-gunAbstract 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.https://doi.org/10.1038/s41598-017-08019-5 |
| spellingShingle | Shin-ichi Terawaki Shohei Fujita Takuya Katsutani Kensuke Shiomi Kazuko Keino-Masu Masayuki Masu Kaori Wakamatsu Naoki Shibata Yoshiki Higuchi Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain Scientific Reports |
| title | Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain |
| title_full | Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain |
| title_fullStr | Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain |
| title_full_unstemmed | Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain |
| title_short | Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain |
| title_sort | structural basis for ccd1 auto inhibition in the wnt pathway through homomerization of the dix domain |
| url | https://doi.org/10.1038/s41598-017-08019-5 |
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