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J. Biol. Chem., Vol. 281, Issue 7, 4087-4093, February 17, 2006

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A Highly Conserved Amino-terminal Region of Sonic Hedgehog Is Required for the Formation of Its Freely Diffusible Multimeric Form^*

John A. Goetz¹, Samer Singh¹, Liza M. Suber^||, F. Jon Kull^¶, and David J. Robbins²

From the Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, ^¶Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, and the ^||University of Cincinnati, College of Medicine, Department of Molecular Genetics, Cincinnati, Ohio 45249

Although members of the Hedgehog (Hh) family were initially described as morphogens, many of these early conclusions were based on experiments that used non-physiologically relevant forms of Hh. Native Hh is modified by cholesterol (HhNp) and palmitate. These hydrophobic modifications are responsible for the ability of Hh to associate with cellular membranes, a property that initially appeared inconsistent with its ability to act far from its site of synthesis. Although it is now clear that Hh family members are capable of acting directly in long-range signaling, the form of Hh capable of this activity remains controversial. We have previously provided evidence for a freely diffusible multimeric form of Sonic Hedgehog (Shh) termed s-ShhNp, which is capable of accumulating in a gradient fashion through a morphogenic field. Here, we provide further evidence that s-ShhNp is the physiologically relevant form of Shh. We show that the biological activity of freely diffusible ShhNp resides in its multimeric form and that this multimeric form is exceedingly stable, even to high concentrations of salt and detergent. Furthermore, we now validate the Shh-Shh interactions previously observed in the crystal structure of human Shh, showing that a highly conserved amino-terminal domain of Shh is important for the formation of s-ShhNp. We also conclusively show that palmitoylation is required for s-ShhNp formation. Thus, our results identify both protein-protein and protein-lipid interactions that are required for s-ShhNp formation, and provide the first structural analyses supporting the existence of Shh multimers.

Received for publication, October 20, 2005 , and in revised form, December 6, 2005.

^* This work was supported by National Institutes of Health Grant RO1-GM64011 (to D. J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Tel.: 603-650-1716; Fax: 603-650-1129; E-mail: David.J.Robbins{at}Dartmouth.edu.

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