Congenital Generalized Lipodystrophy Mutation p.Glu176Argfs Renders Cavin-1 Leucine Zipper Domain 2 to Off-Targets

Caveolae are small membrane invaginations found in vertebrates. Cavin-1 protein is essential for the homeostasis of caveolae. The frameshift mutation (p.Glu176Argfs) cavin-1 leads to physically debilitating condition known as congenital generalized lipodystrophy (CGL). Here we examined leucine zipper domain 2 (LZD2) and its CGL variant potential gain function through interaction with model membranes. Tryptophan fluorescence quenching presence liposomes established higher membrane-binding propensity mutant peptide. A concentrated arginine residues LZD2 region confers a affinity towards negatively charged membrane. Competitive binding studies raft mimicking lipid vesicles showed ability target cholesterol/sphingomyelin-rich domains. These data suggest that may have predisposition off-target membranes disease condition.