Structural insights into proteoglycan-shaped Hedgehog signaling
Whalen DM., Malinauskas T., Gilbert RJC., Siebold C.
Significance The Hedgehog (Hh) signaling pathway plays key roles during embryonic development and remains active in adults. Mutations in the genes encoding the Hh signaling pathway proteins lead to developmental disorders and cancer. The glycosaminoglycan (GAG) chains of proteoglycans at the cell surface shape Hh gradients and signal transduction. We determined the crystal structures of Hh proteins with two different GAG chains, heparin and chondroitin sulfate. The GAG-binding site we identified in the Hh protein is previously not identified and the majority of Hh residues forming this GAG-binding site have been previously implicated in developmental diseases. Analysis of the crystal packing, combined with biophysical experiments, revealed GAG-dependent Hh multimerization and suggests a unique mechanism of Hh signaling regulation.