Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 16, Issue 7, Pages 698-U29Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1607
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Funding
- MRC [G0500365, G0700232, G116/165] Funding Source: UKRI
- Cancer Research UK Funding Source: Medline
- Medical Research Council [G0500365, G116/165, G0700232] Funding Source: Medline
- Wellcome Trust [082301] Funding Source: Medline
- Medical Research Council [G116/165, G0700232, G0500365] Funding Source: researchfish
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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.
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