2WFX

Crystal structure of the complex between human hedgehog-interacting protein HIP and Sonic Hedgehog in the presence of calcium

Summary for 2WFX

• Entry DOI: 10.2210/pdb2wfx/pdb
• Related: 1VHH 2WFT 2WG3 2WG4 2WGQ 2WGR
• Descriptor: SONIC HEDGEHOG PROTEIN N-PRODUCT, HEDGEHOG-INTERACTING PROTEIN, ZINC ION, ... (5 entities in total)
• Functional Keywords: signaling protein, autocatalytic cleavage, protease, membrane, secreted, palmitate, hydrolase, signal transduction, developmental protein, lipoprotein, development, glycoprotein, cell membrane, disulfide bond, egf-like domain, hedgehog signaling
• Biological source: MUS MUSCULUS (MOUSE); More
• Cellular location: Sonic hedgehog protein C-product: Secreted, extracellular space. Sonic hedgehog protein N-product: Cell membrane; Lipid-anchor: Q62226; Cell membrane; Peripheral membrane protein (By similarity). Isoform 2: Cytoplasm (Probable): Q96QV1
• Total number of polymer chains: 2
• Total formula weight: 68592.85

Authors

Bishop, B.,Aricescu, A.R.,Harlos, K.,O'Callaghan, C.A.,Jones, E.Y.,Siebold, C. (deposition date: 2009-04-15, release date: 2009-06-30, Last modification date: 2024-10-23)

Primary citation

Bishop, B.,Aricescu, A.R.,Harlos, K.,O'Callaghan, C.A.,Jones, E.Y.,Siebold, C.
Structural Insights Into Hedgehog Ligand Sequestration by the Human Hedgehog-Interacting Protein Hip
Nat.Struct.Mol.Biol., 16:698-, 2009

PubMed 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.

PubMed: 19561611
DOI: 10.1038/NSMB.1607

Experimental method

X-RAY DIFFRACTION (3.2 Å)