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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Crystallography, X-Ray
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Drosophila Proteins / chemistry*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / chemistry
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism
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Gene Expression Regulation
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HEK293 Cells
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Hedgehog Proteins / chemistry*
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism
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Humans
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Kinetics
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Kruppel-Like Transcription Factors / chemistry*
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Nuclear Proteins / chemistry*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Peptides / chemical synthesis
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Peptides / genetics
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Peptides / metabolism
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Protein Interaction Domains and Motifs
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Repressor Proteins / chemistry*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Sequence Alignment
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Sequence Homology, Amino Acid
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Signal Transduction*
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Thermodynamics
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Transcription Factors / chemistry*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
Substances
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Drosophila Proteins
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GLI1 protein, human
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GLI2 protein, human
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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Peptides
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Repressor Proteins
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SUFU protein, human
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Su(fu) protein, Drosophila
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Transcription Factors
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
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hh protein, Drosophila
Associated data
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PDB/4KM8
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PDB/4KM9
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PDB/4KMA
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PDB/4KMD
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PDB/4KMH