Article abstract
Nature Structural & Molecular Biology 16, 698 - 703 (2009)
Published online: 28 June 2009 | doi:10.1038/nsmb.1607
Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP
Benjamin Bishop1, A Radu Aricescu1, Karl Harlos1, Chris A O'Callaghan2, E Yvonne Jones1 & Christian Siebold1
Abstract
Hedgehog (Hh) morphogens have fundamental roles in development, whereas dysregulation of Hh signaling leads to disease. Multiple cell-surface receptors are responsible for transducing and/or regulating Hh signals. Among these, the Hedgehog-interacting protein (Hhip) is a highly conserved, vertebrate-specific inhibitor of Hh signaling. We have solved a series of crystal structures for the human HHIP ectodomain and Desert hedgehog (DHH) in isolation, as well as HHIP in complex with DHH (HHIP–DHH) and Sonic hedgehog (Shh) (HHIP–Shh), with and without Ca2+. The interaction determinants, confirmed by biophysical studies and mutagenesis, reveal previously uncharacterized and distinct functions for the Hh Zn2+ and Ca2+ binding sites—functions that may be common to all vertebrate Hh proteins. Zn2+ makes a key contribution to the Hh–HHIP interface, whereas Ca2+ is likely to prevent electrostatic repulsion between the two proteins, suggesting an important modulatory role. This interplay of several metal binding sites suggests a tuneable mechanism for regulation of Hh signaling.
- Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
- Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
Correspondence to: Christian Siebold1 e-mail: christian@strubi.ox.ac.uk
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