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Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. Andrea Gorrell.

Contents 1 Sonic Hedgehog 1.1 Introduction 1.2 Structural Overview 1.3 Signaling Pathway 2 References

Sonic Hedgehog

Template:STRUCTURE 1vhh

Introduction

Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins that serve important roles in regulating both short-range and long-range patterning processes in developing invertebrate and vertebrate tissues ^[1]. First discovered in Drosophila, where mutations of the Hedgehog gene produces larvae that are covered in hedgehog-like denticles, Hh proteins are encoded by at least three genes in mammals - Sonic, Desert, and Indian hedgehog ^[2]. With the ability to control such fundamental processes as pattern formation in vertebrate limb buds, the formation of motor neurons in the neural tube, and the development and maintenance of tissues and organs, Shh is the most well-studied member of the Hh signaling pathway (2). Excessive signaling in adult cells has been implicated in the development of several human cancers ^[3][4].

As with all members of the Hh family, Shh biosynthesis begins with an unusual molecular processing event involving the autocatalytic cleavage of the Shh precursor protein into a 19-kDa amino-terminal domain (Shh-N) and a 27-kDa C-terminal domain (Shh-C) ^[5]. Spanning residues 24 to 197 in human Shh, Shh-N is responsible for all of the local and long-range signaling activities of Shh. Shh-C possesses an intramolecular transferase activity responsible for covalent attachment of a molecule of cholesterol to the C-terminus of Shh-N. Addition of cholesterol serves to tether Shh-N to the cell membrane, restricting its range of activity to that of local signaling only ^[6]. Thus, the two domains of Shh are catalytically distinct.

Structural Overview

The proposed structure for the native Shh-N protein (1VHH) from Cys 25 to Gly 198 is shown. An α + β sandwich consisting of two and a six-stranded, mixed with long connecting loops makes up the core of the structure, along with a two-stranded, antiparallel β-sheet. Although this type of folding arrangement has not yet been seen in other proteins, the presence of a in Shh-N bears close structural resemblance to the zinc coordination sites of zinc hydrolases, including thermolysin and carboxypeptidase A. Three amino acid side chains – – are bound to the zinc ion in the crystal structure, along with a single . Zinc ions that serve a structural role in proteins are normally coordinated by four amino acid side chains, including a cysteine, and are not usually exposed to the surrounding solvent. The coordinated zinc in Shh-N, by contrast, is suggested to possess a catalytic function on account of its exposure to the solvent and its coordination to a water molecule in the crystal structure instead of a fourth amino acid residue. In zinc hydrolases, a zinc-bound water molecule is key to the protein's enzymatic activity when its proton is removed by a nearby glutamate residue. Glu177 is believed to serve an analogous role in Shh-N, further supporting a novel, hydrolytic function for this protein. Other residues in Shh-N that may serve a similar catalytic role to those in zinc hydrolases include His 135, His 181, and Glu 127.

Signaling Pathway

References

1. ↑ Perrimon N. Hedgehog and beyond. Cell. 1995 Feb 24;80:517-520
2. ↑ Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, Mcmahon JA, Mcmahon AP. Sonic Hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993. 75:1417-30
3. ↑ Altaba AR, Sanchez P, Dahmane N. GLI and Hedgehog in cancer: tumours, embryos stem cells. Nature Reviews Cancer. 2002 May;2:361-372
4. ↑ di Magliano MP, Hebrok, M. Nature Reviews Cancer. 2003 December;3:903-911
5. ↑ Bumcrot DA, Takada R, McMahon AP. Proteolytic processing yields two secreted forms of sonic hedgehog. 1995 April;15(4);2294-2302
6. ↑ Porter JA, Young KE, Beachy PA. Cholesterol modification of hedgehog signalling proteins in animal development. Science. 1996 Oct 11;274:255-259