The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla

Jason S. McLellan, Xiaoyan Zheng, Glenn Hauk, Rodolfo Ghirlando, Philip A. Beachy, Daniel J. Leahy

Research output: Contribution to journalArticle

Abstract

Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.

Original languageEnglish (US)
Pages (from-to)979-983
Number of pages5
JournalNature
Volume455
Issue number7215
DOIs
StatePublished - Oct 16 2008

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Hedgehogs
Hedgehog Proteins
Fibronectins
Drosophila
Vertebrates
Hip
Holoprosencephaly
Calcium
Lipoproteins
Heparin
Immunoglobulins
Mammals
Membrane Proteins
Embryonic Structures
Binding Sites
X-Rays
Mutation

ASJC Scopus subject areas

  • General

Cite this

McLellan, J. S., Zheng, X., Hauk, G., Ghirlando, R., Beachy, P. A., & Leahy, D. J. (2008). The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature, 455(7215), 979-983. https://doi.org/10.1038/nature07358

The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. / McLellan, Jason S.; Zheng, Xiaoyan; Hauk, Glenn; Ghirlando, Rodolfo; Beachy, Philip A.; Leahy, Daniel J.

In: Nature, Vol. 455, No. 7215, 16.10.2008, p. 979-983.

Research output: Contribution to journalArticle

McLellan, JS, Zheng, X, Hauk, G, Ghirlando, R, Beachy, PA & Leahy, DJ 2008, 'The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla', Nature, vol. 455, no. 7215, pp. 979-983. https://doi.org/10.1038/nature07358
McLellan JS, Zheng X, Hauk G, Ghirlando R, Beachy PA, Leahy DJ. The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature. 2008 Oct 16;455(7215):979-983. https://doi.org/10.1038/nature07358
McLellan, Jason S. ; Zheng, Xiaoyan ; Hauk, Glenn ; Ghirlando, Rodolfo ; Beachy, Philip A. ; Leahy, Daniel J. / The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. In: Nature. 2008 ; Vol. 455, No. 7215. pp. 979-983.
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