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.
Highlights
The Hedgehog (Hh1) signalling pathway plays a key role in directing cellular growth and tissue patterning during embryonic development
A crystal structure of an N-terminal domain of SUFU has been reported (Merchant et al, 2004), no information is available on its C-terminal region and how this is arranged relative to the rest of the protein owing to difficulties in producing soluble full-length recombinant protein
We have expressed an essentially full-length human SUFU construct in E. coli by fusing it to an N-terminal maltosebinding protein (MBP) molecule via a three-alanine linker (Smyth et al, 2003; Monneet al., 2008)
Summary
The Hedgehog (Hh1) signalling pathway plays a key role in directing cellular growth and tissue patterning during embryonic development. A Hh ligand binds to the membrane receptor Patched (Ptc), which in the unliganded state represses another transmembrane protein, Smoothened (Smo). This repression is relieved upon ligand binding, allowing active Smo to regulate transcriptionfactor activity. Whilst being completely dispensable for Drosophila embryogenesis, this protein is absolutely essential for doi:10.1107/S0907444913028473 2563 research papers mammalian development, since knockout of Sufu in mice leads to continuous ligand-independent Hh signalling activity and embryonic lethality at $E9.5 (Cooper et al, 2005; Svard et al, 2006). Loss of human SUFU activity is associated with multiple cancer forms. Somatic mutations and loss have been found in medulloblastoma, chondrosarcoma and rhabdomyosarcoma (Taylor et al, 2002; Tostar et al, 2006; Tarpey et al, 2013)
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