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.
Original language | English |
---|---|
Pages (from-to) | 698-703 |
Number of pages | 6 |
Journal | Nature Structural & Molecular Biology |
Volume | 16 |
Issue number | 7 |
DOIs | |
Publication status | Published - Jul 2009 |
Keywords
- Animals
- Binding Sites
- Calcium
- Carrier Proteins
- Hedgehog Proteins
- Humans
- Ligands
- Membrane Glycoproteins
- Models, Molecular
- Molecular Sequence Data
- Multiprotein Complexes
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Zinc