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.

DOI

10.1073/pnas.1310097110

Type

Journal article

Journal

Proceedings of the National Academy of Sciences

Publisher

Proceedings of the National Academy of Sciences

Publication Date

08/10/2013

Volume

110

Pages

16420 - 16425

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