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Structural Basis of SUFU–GLI Interaction in Human Hedgehog Signalling Regulation

Cherry, Amy and Finta, C. and Karlström, M. and Jin, Q. and Schwend, T. and Astorga-Wells, J. and Zubarev, R.A. and Del Campo, M. and Criswell, A.R. and de Sanctis, D. and Jovine, L. and Toftgård, R. (2013) Structural Basis of SUFU–GLI Interaction in Human Hedgehog Signalling Regulation. Acta Crystallographica Section D: Biological Crystallography, 69 (12). pp. 2563-2579. ISSN Print: 0907-4449 Online: 1399-0047

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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 smallangle 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.

Item Type: Article
Uncontrolled Keywords: Hedgehog signalling pathway, cancer, development, SUFU, GLI, Hedgehog signalling regulation
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Academic Departments > Institute of Science and the Environment
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Copyright Info: Open Access article
Depositing User: Amy Cherry
Date Deposited: 26 Nov 2013 10:32
Last Modified: 27 Nov 2014 14:07
URI: https://eprints.worc.ac.uk/id/eprint/2746

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