Site-Directed Mutagenesis of the Hydrophobic Cleft of Perilipin 5

Type II diabetes mellitus, non-alcoholic fatty liver disease, obesity, and heart disease are all affected by atypical lipid storage. Lipid storage droplets are found in most somatic cells, however problems can arise. An example of this is abnormal fat distribution termed lipodystrophy [2]. The structure of these droplets include a hydrophobic core surrounded by a phospholipid monolayer studded with several proteins that regulate the formation and breakdown of the droplet. Perilipin 5 is a lipid droplet protein that plays a key role in lipid storage and mobilization in oxidative tissues within the fasted state. The perilipin protein family is encoded by five highly regulated genes. Perilipin 3, a member of this family, has had its structure solved. The structure of the C-terminus of perilipin 3 consists of a four-helix bundle domain and a mixed alpha-beta structure. At the interface of these two units is a hydrophobic cleft. Perilipin 5’s sequence is similar to perilipin 3. Therefore, the structure is conserved between them, and the hydrophobic cleft is present. Additionally, this modeled structure retains features of perilipin 3 including the four-helix bundle and mixed alpha beta domain. Differences can be found in that the cleft of perilipin 5 contains a potentially different amino acid sequence as well as a short insertion, which may affect this pocket. Ongoing studies seek to generate mutations to this cleft to probe the function of this structural feature in perilipin 5.