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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Autores principales:	Shin-ichi Terawaki, Shohei Fujita, Takuya Katsutani, Kensuke Shiomi, Kazuko Keino-Masu, Masayuki Masu, Kaori Wakamatsu, Naoki Shibata, Yoshiki Higuchi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/82ea2c14f6a04fdfac2aa1e522bd3b63
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spelling	oai:doaj.org-article:82ea2c14f6a04fdfac2aa1e522bd3b632021-12-02T12:32:42ZStructural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain10.1038/s41598-017-08019-52045-2322https://doaj.org/article/82ea2c14f6a04fdfac2aa1e522bd3b632017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08019-5https://doaj.org/toc/2045-2322Abstract 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.Shin-ichi TerawakiShohei FujitaTakuya KatsutaniKensuke ShiomiKazuko Keino-MasuMasayuki MasuKaori WakamatsuNaoki ShibataYoshiki HiguchiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	structural basis for ccd1 auto-inhibition in the wnt pathway through homomerization of the dix domain
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/82ea2c14f6a04fdfac2aa1e522bd3b63
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Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain

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