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Title: Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation. 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:
; ; ; ;  [1] ;  [2] ;  [3] ;  [2] ; ;  [4] ;  [5] ; ;  [1]
  1. Karolinska Institutet, Novum, Hälsovägen 7, SE-141 83 Huddinge (Sweden)
  2. Karolinska Institutet, Scheeles väg 2, SE-171 77 Stockholm (Sweden)
  3. (Sweden)
  4. Rigaku Americas Corporation, 9009 New Trails Drive, The Woodlands, TX 77381 (United States)
  5. European Synchrotron Radiation Facility, 6 Rue Jules Horowitz, 38043 Grenoble (France)
Publication Date:
OSTI Identifier:
22347808
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 69; Journal Issue: Pt 12; Other Information: PMCID: PMC3852661; PMID: 24311597; PUBLISHER-ID: dw5072; OAI: oai:pubmedcentral.nih.gov:3852661; Copyright (c) Cherry et al. 2013; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CELL PROLIFERATION; CONFORMATIONAL CHANGES; CRYSTALS; INTERACTIONS; INTERFACES; LENGTH; NEOPLASMS; SCATTERING