Sonic Hedgehog

From Proteopedia

Revision as of 07:03, 16 March 2010

Sonic Hedgehog

Introduction

Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted extracellular signaling proteins that serve important roles in controlling cell differentiation, proliferation, and gene expression in animal embryos and adult 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 vertebrates - Sonic, Desert, and Indian hedgehog. 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).

As with all members of the Hh family, Shh biosynthesis begins with a molecular processing event involving the autocatalytic cleavage of the Shh precursor protein into a 19-kDa amino-terminal domain (Shh-N) and a 25-kDa C-terminal domain (Shh-C). 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. Thus, the two domains of Shh are catalytically distinct (4,5).

Structural Overview

The proposed structure for the native Shh-N protein from Cys 25 to Gly 198 is shown in Figure 1. An α + β sandwich consisting of two α-helices and a six-stranded, mixed β-sheet with long connecting loops comprises the core of the structure, along with a single two-stranded, antiparallel β-sheet.