Structure of a heparin-dependent complex of hedgehog and Ihog

Jason S. McLellan, Shenqin Yao, Xiaoyan Zheng, Brian V. Geisbrecht, Rodolfo Ghirlando, Philip A. Beachy, Daniel J. Leahy

Research output: Contribution to journalArticlepeer-review

Abstract

Hedgehog (Hh) signaling molecules mediate key tissue-patterning events during animal development, and inappropriate activation of Hh signaling in adults has been associated with human cancers. Recently, a conserved family of type I integral membrane proteins required for normal response to the Hh signal was discovered. One member of this family, Ihog (interference hedgehog), functions upstream or at the level of Patched (Ptc), but how Ihog participates in Hh signaling remains unclear. Here, we show that heparin binding induces Ihog dimerization and is required to mediate high-affinity interactions between Ihog and Hh. We also present crystal structures of a Hh-binding fragment of Ihog, both alone and complexed with Hh. Heparin is not well ordered in these structures, but a basic cleft in the first FNIII domain of Ihog (IhogFn1) is shown by mutagenesis to mediate heparin binding. These results establish that Hh directly binds Ihog and provide the first demonstration of a specific role for heparin in Hh responsiveness.

Original languageEnglish (US)
Pages (from-to)17208-17213
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number46
DOIs
StatePublished - Nov 14 2006

Keywords

  • Heparan sulfate proteoglycan
  • Signaling

ASJC Scopus subject areas

  • General

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