Open AccessStructural basis of SUFU–GLI interaction in human Hedgehog signalling regulation
Author(s) -
Cherry Amy L.,
Finta Csaba,
Karlström Mikael,
Jin Qianren,
Schwend Thomas,
AstorgaWells Juan,
Zubarev Roman A.,
Del Campo Mark,
Criswell Angela R.,
de Sanctis Daniele,
Jovine Luca,
Toftgård Rune
Publication year - 2013
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s0907444913028473
Subject(s) - hedgehog , hedgehog signaling pathway , biology , microbiology and biotechnology , regulator , transcription factor , signalling , intracellular , gli1 , signal transduction , genetics , gene
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.