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

2013; Nature Portfolio; Volume: 4; Issue: 1 Linguagem: Inglês

10.1038/ncomms3608

2041-1723

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

Oral and Maxillofacial Pathology

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. Suppressor of Fused (Sufu) controls the nucleocytoplasmic distribution of Gli transcription factors in response to Hedgehog signalling. Zhang et al.report crystal structures of the Sufu/Gli complex, and show that Sufu transitions from an open to a closed form in response to Gli binding.