2WFQ

Crystal structure of the N-terminal signalling domain of human Dhh without calcium

Summary for 2WFQ

• Entry DOI: 10.2210/pdb2wfq/pdb
• Related: 2WFR 2WFT 2WFX 2WG3 2WG4
• Descriptor: DESERT HEDGEHOG PROTEIN N-PRODUCT, ZINC ION, SULFATE ION, ... (4 entities in total)
• Functional Keywords: lipoprotein, development, cell membrane, autocatalytic cleavage, signaling protein, disease mutation, hedgehog signalling, protease, membrane, secreted, palmitate, hydrolase, signal transduction, developmental protein
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 19010.55

Authors

Bishop, B.,Aricescu, A.R.,Harlos, K.,O'Callaghan, C.A.,Jones, E.Y.,Siebold, C. (deposition date: 2009-04-14, release date: 2009-06-30, Last modification date: 2023-12-13)

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 (1.85 Å)