Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation

• Published in: Acta crystallographica. Section D, Biological crystallography. Vol. 69; no. 12; pp. 2563 - 2579
• Main Authors: Cherry, Amy L., Finta, Csaba, Karlström, Mikael, Jin, Qianren, Schwend, Thomas, Astorga-Wells, Juan, Zubarev, Roman A., Del Campo, Mark, Criswell, Angela R., de Sanctis, Daniele, Jovine, Luca, Toftgård, Rune
• Format: Journal Article
• Language: English
• Published: 5 Abbey Square, Chester, Cheshire CH1 2HU, England International Union of Crystallography 01.12.2013; Wiley Subscription Services, Inc
• Subjects: Amino Acid Sequence; Animals; Binding; CELL PROLIFERATION; CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CONFORMATIONAL CHANGES; Control; Crystallography, X-Ray; CRYSTALS; Deregulation; GLI; Hedgehog signalling regulation; Hedgehogs - metabolism; Human; Humans; INTERACTIONS; INTERFACES; LENGTH; Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Models, Molecular; Modulators; Molecular Sequence Data; NEOPLASMS; Pathways; Protein Conformation; Protein Interaction Maps; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Research Papers; SCATTERING; Signal Transduction; Signalling; SUFU; Transcription Factors - chemistry; Transcription Factors - metabolism; Zinc Finger Protein GLI1; GLI; Hedgehog signalling regulation; SUFU
• ISSN: 1399-0047; 0907-4449; 1399-0047
• DOI: 10.1107/S0907444913028473

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.