Publication

Article Metrics

Citations


Online attention

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

DOI: 10.1038/nsmb.1607 DOI Help
PMID: 19561611 PMID Help

Authors: B. Bishop (Wellcome Trust Centre for Human Genetics, University of Oxford) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , C. A. O'callaghan (Wellcome Trust Centre for Human Genetics, University of Oxford) , E. Y. Jones (Wellcome Trust Centre for Human Genetics, University of Oxford) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford) , Alexandru Aricescu (Wellcome Trust Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 16 (7) , PAGES 698 - 703

State: Published (Approved)
Published: June 2009

Open Access Open Access

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 Ca(2+). The interaction determinants, confirmed by biophysical studies and mutagenesis, reveal previously uncharacterized and distinct functions for the Hh Zn(2+) and Ca(2+) binding sites-functions that may be common to all vertebrate Hh proteins. Zn(2+) makes a key contribution to the Hh - HHIP interface, whereas Ca(2+) 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.

Journal Keywords: Binding; Calcium; Carrier; Hedgehog; Humans; Ligands; Membrane; Models; Molecular; MultiProtein; Secondary; Protein; Tertiary; Zinc

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography