The Structural Determination of an Insect Sterol Carrier Protein-2 with a Ligand-bound C16 Fatty Acid at 1.35-Å Resolution

Abstract Yellow fever mosquito sterol carrier protein (SCP-2) is known to bind to cholesterol. We report here the three-dimensional structure of the complex of SCP-2 from Aedes aegypti with a C16 fatty acid to 1.35-A resolution. The protein fold is exceedingly similar to the human and rabbit proteins, which consist of a five-stranded β-sheet that exhibits strand order 3-2-1-4-5 with an accompanying layer of four α-helices that cover the β-sheet. A large cavity exists at the interface of the layer α-helices and the β-sheet, which serves as the fatty acid binding site. The carboxylate moiety of the fatty acid is coordinated by a short loop that connects the first α-helix to the first β-strand, whereas the acyl chain extends deep into the interior of the protein. Interestingly, the orientation of the fatty acid is opposite to the observed orientation for Triton X-100 in the SCP-2-like domain from the peroxisomal multifunctional enzyme (Haapalainen, A. M., van Aalten, D. M., Merilainen, G., Jalonen, J. E., Pirila, P., Wierenga, R. K., Hiltunen, J. K., and Glumoff, T. (2001) J. Mol. Biol. 313, 1127-1138). The present study suggests that the binding pocket in the SCP-2 family of proteins may exhibit conformational flexibility to allow coordination of a variety of lipids.