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

Benjamin Bishop, Alexandru R Aricescu, Karl Harlos, Chris A O'Callaghan, E Yvonne Jones, Christian Siebold

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)698-703
Number of pages6
JournalNature Structural & Molecular Biology
Volume16
Issue number7
DOIs
Publication statusPublished - 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

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