CHOLESTEROL MODIFICATION OF HEDGEHOG SIGNALING PROTEINS IN ANIMAL DEVELOPMENT

Hedgehog (Hh) proteins comprise a family of secreted signaling molecul es essential for patterning a variety of structures in animal embryoge nesis. During biosynthesis, Hh undergoes an autocleavage reaction, med iated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activit y. Here it is reported that cholesterol is the lipophilic moiety coval ently attached to the amino-terminal signaling domain during autoproce ssing and that the carboxyl-terminal domain acts as an intramolecular cholesterol transferase. This use of cholesterol to modify embryonic s ignaling proteins may account for some of the effects of perturbed cho lesterol biosynthesis on animal development.