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Title: Structure of a Heparin-dependent Complex of Hedgehog and Ihog

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.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930141
Report Number(s):
BNL-80795-2008-JA
TRN: US200822%%1346
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the USA; Journal Volume: 103; Journal Issue: 46
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ADULTS; ANIMALS; BASIC; CRYSTAL STRUCTURE; DIMERIZATION; FUNCTIONS; HEPARIN; HUMAN POPULATIONS; INTEGRALS; INTERACTIONS; INTERFERENCE; LEVELS; MEMBRANE PROTEINS; MOLECULES; MUTAGENESIS; SIGNALS; national synchrotron light source

Citation Formats

McLellan,J., Yao, S., Zheng, X., Geisbrecht, B., Ghirlando, R., Beachy, P., and Leahy, D.. Structure of a Heparin-dependent Complex of Hedgehog and Ihog. United States: N. p., 2006. Web. doi:10.1073/pnas.0606738103.
McLellan,J., Yao, S., Zheng, X., Geisbrecht, B., Ghirlando, R., Beachy, P., & Leahy, D.. Structure of a Heparin-dependent Complex of Hedgehog and Ihog. United States. doi:10.1073/pnas.0606738103.
McLellan,J., Yao, S., Zheng, X., Geisbrecht, B., Ghirlando, R., Beachy, P., and Leahy, D.. Sun . "Structure of a Heparin-dependent Complex of Hedgehog and Ihog". United States. doi:10.1073/pnas.0606738103.
@article{osti_930141,
title = {Structure of a Heparin-dependent Complex of Hedgehog and Ihog},
author = {McLellan,J. and Yao, S. and Zheng, X. and Geisbrecht, B. and Ghirlando, R. and Beachy, P. and Leahy, D.},
abstractNote = {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.},
doi = {10.1073/pnas.0606738103},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 46,
volume = 103,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}