title: Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation.
abstract: Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU-GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU-GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.
authors: Department of Biosciences and Nutrition and Center for Biosciences, Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge, Sweden.
authors: Amy L
authors: AL
authors: Cherry
authors: Csaba
authors: C
authors: Finta
authors: Mikael
authors: M
authors: Karlström
authors: Qianren
authors: Q
authors: Jin
authors: Thomas
authors: T
authors: Schwend
authors: Juan
authors: J
authors: Astorga-Wells
authors: Roman A
authors: RA
authors: Zubarev
authors: Mark
authors: M
authors: Del Campo
authors: Angela R
authors: AR
authors: Criswell
authors: Daniele
authors: D
authors: de Sanctis
authors: Luca
authors: L
authors: Jovine
authors: Rune
authors: R
authors: Toftgård
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D006364:Hedgehogs / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D060066:Protein Interaction Maps; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D012097:Repressor Proteins; C490764:SUFU protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
keywords: GLI; Hedgehog signalling regulation; SUFU