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 () and Geng Wu ()
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Yan Zhang: State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Lin Fu: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Xiaolong Qi: State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Zhenyi Zhang: State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University
Yuanxin Xia: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Jianhang Jia: Markey Cancer Center, University of Kentucky
Jin Jiang: University of Texas Southwestern Medical Center at Dallas
Yun Zhao: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Geng Wu: State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3608

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