Title : Structural insights into hedgehog ligand sequestration by the human
hedgehog-interacting protein HHIP
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