Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development

Abstract

Hedgehog (Hh) proteins comprise a family of secreted signaling molecules essential for patterning a variety of structures in animal embryogenesis. During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. Here it is reported that cholesterol is the lipophilic moiety covalently attached to the amino-terminal signaling domain during autoprocessing and that the carboxyl-terminal domain acts as an intramolecular cholesterol transferase. This use of cholesterol to modify embryonic signaling proteins may account for some of the effects of perturbed cholesterol biosynthesis on animal development.

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

“…[9][10][11][12][13] Human defects in the 7-dehydrocholesterol pathway leading to SLOS (MIM 270400) have been well described. Far less common are human defects in DHCR24, encoding the enzyme 3b-hydroxysterol D 24 -reductase, which catalyses the reduction of desmosterol to form cholesterol.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Following translation, Hh proteins enter the secretory pathway and undergo autoprocessing and lipid modifications that produce a signaling peptide modified at its both ends by palmitoyl (N terminus) and cholesteryl (C terminus) adducts (Lee et al, 1994;Porter et al, 1995Porter et al, , 1996Buglino and Resh, 2008). The movement of Hh proteins is regulated by several molecules, such as the transmembrane transporter-like protein Dispatched (Disp) (11)(12)(13)(14) and metalloproteases (Dierker et al, 2009) for release of Hh from secreting cells, the heparan sulfate proteoglycans Dally-like (Dlp) and Dally (Lum et al, 2003;Beckett et al, 2008) or their regulators (Baena-Lopez et al, 2008) for extracellular transport of Hh protein as well as enzymes such as Sulfateless and Tout velu for heparan sulfate biosynthesis (Bellaiche et al, 1998;Toyoda et al, 2000;Koziel et al, 2004).…”

Anteroposterior patterning in the limb and digit specification: Contribution of mouse genetics

“…Production of an active Shh signal requires autoproteolytic cleavage of the full-length Shh protein that releases a 19-kDa N-terminal fragment (Bumcrot et al, 1995). The latter is associated to the cell surface by cholesterol and fatty acids that are covalently bound to its C-terminus (Porter et al, 1996;Pepinsky et al, 1998). Lewis et al (2001) constructed a mutant mouse strain that constitutively produces a truncated Shh protein (NShh), which cannot undergo cholesterol modification.…”