Molecular Evolution of Sterol-Sensing Domain in Eukaryotes

The sterol-sensing domain (SSD) is a ∼180 amino acid long region that is conserved in six families of proteins such as hydroxymethylglutaryl-CoA reductase (HMDH), SREBP (sterol regulatory element binding protein) cleavage activating protein (SCAP), Niemann-Pick C-1 type protein (NPC1), Patched, Patched-related and Dispatched [1]. This domain encompasses five transmembrane helices and is involved in sterol-level sensing in the cell. All these classes of proteins thus have functions related to sterols. HMDH is a cholesterol biosynthetic enzyme that is degraded when sterol levels are high. SCAP is responsible for regulating SREBP, a transcription factor of cholesterol biosynthetic genes. NPC1 is responsible for intracellular transport of cholesterol. Patched plays a role in cell differentiation during development and morphogenesis. It is a receptor of hedgehog, a ligand that is bound to cholesterol. Dispatched is involved in releasing the cholesterol-bound hedgehog. The importance of SSD in proper functioning of these proteins has been shown by various mutation experiments. For example, mutations in the SSD region of NPC1 disrupt normal transportation of cholesterol in the cells [2]. Mutation in SSD can be lethal to cells and cause various diseases due to the abruption of cholesterol homeostasis in cells. The role of SSD in sterol homeostasis in cells makes it an important target for bio-medical research in understanding and curing cholesterol-related diseases. Despite its importance, SSD has not been thoroughly studied in its own entirety. In order to elucidate the molecular evolution of SSD and related protein families, in this study we examined SSDs in various eukaryotic species as well as in different protein families. Existence of HMDH proteins with and without SSDs, for example, provided us with an excellent opportunity to study how their functions and domains have been acquired during the evolution of this protein family.