Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci

Yan Zhang; Lin Fu; Xiaolong Qi; Zhenyi Zhang; Yuanxin Xia; Jianhang Jia; Jin Jiang; Yun Zhao; Geng Wu

doi:10.1038/ncomms3608

Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci

Yan Zhang, Lin Fu, Xiaolong Qi, Zhenyi Zhang, Yuanxin Xia, Jianhang Jia, Jin Jiang, Yun Zhao, Geng Wu

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

Abstract

Hedgehog (Hh) signalling regulates embryonic development and adult tissue homoeostasis. Mutations of its pathway components including Suppressor of Fused (Sufu) and Gli/Ci predispose to cancers and congenital anomalies. The Sufu-Gli protein complex occupies a central position in the vertebrate Hh signalling pathway, especially in mammals. Here structures of full-length human and Drosophila Sufu, the human Sufu-Gli complex, along with normal mode analysis and FRET measurement results, reveal that Sufu alternates between 'open' and 'closed' conformations. The 'closed' form of Sufu is stabilized by Gli binding and inhibited by Hh treatment, whereas the 'open' state of Sufu is promoted by Gli-dissociation and Hh signalling. Mutations of critical interface residues disrupt the Sufu-Gli complex and prevent Sufu from repressing Gli-mediated transcription, tethering Gli in the cytoplasm and protecting Gli from the 26S proteasome-mediated degradation. Our study thus provides mechanistic insight into the mutual recognition and regulation between Sufu and Gli/Ci.

Original language	English (US)
Article number	2608
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3608
State	Published - 2013

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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@article{6ee133cd9a4842c6bc274675f57ef014,

title = "Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci",

abstract = "Hedgehog (Hh) signalling regulates embryonic development and adult tissue homoeostasis. Mutations of its pathway components including Suppressor of Fused (Sufu) and Gli/Ci predispose to cancers and congenital anomalies. The Sufu-Gli protein complex occupies a central position in the vertebrate Hh signalling pathway, especially in mammals. Here structures of full-length human and Drosophila Sufu, the human Sufu-Gli complex, along with normal mode analysis and FRET measurement results, reveal that Sufu alternates between 'open' and 'closed' conformations. The 'closed' form of Sufu is stabilized by Gli binding and inhibited by Hh treatment, whereas the 'open' state of Sufu is promoted by Gli-dissociation and Hh signalling. Mutations of critical interface residues disrupt the Sufu-Gli complex and prevent Sufu from repressing Gli-mediated transcription, tethering Gli in the cytoplasm and protecting Gli from the 26S proteasome-mediated degradation. Our study thus provides mechanistic insight into the mutual recognition and regulation between Sufu and Gli/Ci.",

author = "Yan Zhang and Lin Fu and Xiaolong Qi and Zhenyi Zhang and Yuanxin Xia and Jianhang Jia and Jin Jiang and Yun Zhao and Geng Wu",

note = "Funding Information: We thank Junchen Meng, Ying An and Zhijie Wu for their contributions to this work. We thank Feng Yu, Sheng Huang, Jianhua He and other staff at the beamline BL17U1 at Shanghai Synchrotron Radiation Facility. This work was supported by grants from the National Basic Research Programme of China (the 973 Programme, grant numbers 2013CB733902, 2011CB943902 and 2010CB912101), the National Natural Science Foundation of China (grant numbers 31230002, 31171414 and 31371492) and the {\textquoteleft}Strategic Priority Research Programme{\textquoteright} of the Chinese Academy of Sciences (grant number XDA01010405).",

year = "2013",

doi = "10.1038/ncomms3608",

language = "English (US)",

volume = "4",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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T1 - Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci

AU - Zhang, Yan

AU - Fu, Lin

AU - Qi, Xiaolong

AU - Zhang, Zhenyi

AU - Xia, Yuanxin

AU - Jia, Jianhang

AU - Jiang, Jin

AU - Zhao, Yun

AU - Wu, Geng

N1 - Funding Information: We thank Junchen Meng, Ying An and Zhijie Wu for their contributions to this work. We thank Feng Yu, Sheng Huang, Jianhua He and other staff at the beamline BL17U1 at Shanghai Synchrotron Radiation Facility. This work was supported by grants from the National Basic Research Programme of China (the 973 Programme, grant numbers 2013CB733902, 2011CB943902 and 2010CB912101), the National Natural Science Foundation of China (grant numbers 31230002, 31171414 and 31371492) and the ‘Strategic Priority Research Programme’ of the Chinese Academy of Sciences (grant number XDA01010405).

PY - 2013

Y1 - 2013

N2 - Hedgehog (Hh) signalling regulates embryonic development and adult tissue homoeostasis. Mutations of its pathway components including Suppressor of Fused (Sufu) and Gli/Ci predispose to cancers and congenital anomalies. The Sufu-Gli protein complex occupies a central position in the vertebrate Hh signalling pathway, especially in mammals. Here structures of full-length human and Drosophila Sufu, the human Sufu-Gli complex, along with normal mode analysis and FRET measurement results, reveal that Sufu alternates between 'open' and 'closed' conformations. The 'closed' form of Sufu is stabilized by Gli binding and inhibited by Hh treatment, whereas the 'open' state of Sufu is promoted by Gli-dissociation and Hh signalling. Mutations of critical interface residues disrupt the Sufu-Gli complex and prevent Sufu from repressing Gli-mediated transcription, tethering Gli in the cytoplasm and protecting Gli from the 26S proteasome-mediated degradation. Our study thus provides mechanistic insight into the mutual recognition and regulation between Sufu and Gli/Ci.

AB - Hedgehog (Hh) signalling regulates embryonic development and adult tissue homoeostasis. Mutations of its pathway components including Suppressor of Fused (Sufu) and Gli/Ci predispose to cancers and congenital anomalies. The Sufu-Gli protein complex occupies a central position in the vertebrate Hh signalling pathway, especially in mammals. Here structures of full-length human and Drosophila Sufu, the human Sufu-Gli complex, along with normal mode analysis and FRET measurement results, reveal that Sufu alternates between 'open' and 'closed' conformations. The 'closed' form of Sufu is stabilized by Gli binding and inhibited by Hh treatment, whereas the 'open' state of Sufu is promoted by Gli-dissociation and Hh signalling. Mutations of critical interface residues disrupt the Sufu-Gli complex and prevent Sufu from repressing Gli-mediated transcription, tethering Gli in the cytoplasm and protecting Gli from the 26S proteasome-mediated degradation. Our study thus provides mechanistic insight into the mutual recognition and regulation between Sufu and Gli/Ci.

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Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci

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