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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.

Original publication

DOI

10.1038/nsmb.1607

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

07/2009

Volume

16

Pages

698 - 703

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