Surface properties of adipocyte lipid-binding protein: Response to lipid binding, and comparison with homologous proteins

Adipocyte lipid-binding protein (ALBP) is one of a family of intracellular lipid-binding proteins (iLBPs) that bind fatty acids, retinoids, and other hydrophobic ligands. The different members of this family exhibit a highly conserved three dimensional structure; and where structures have been deter mined both with (holo) and without (apo) bound lipid, observed conformation al changes are extremely small (Banaszak, et al., 1994, Adv. Prot. Chem. 45 , 89; Bernlohr, et al., 1997, Annu. Rev. Nutr. 17, 277). We have examined t he electrostatic, hydrophobic, and water accessible surfaces of ALBP in the apo form and of hole forms with a variety of bound ligands. These calculat ions reveal a number of previously unrecognized changes between apo and hol e ALBP, including: 1) an increase in the overall protein surface area when Ligand binds, 2) expansion of the binding cavity when ligand is bound, 3) c lustering of individual residue exposure increases in the area surrounding the proposed ligand entry portal, and 4) ligand-binding dependent variation in the topology of the electrostatic potential in the area surrounding the ligand entry portal. These focused analyses of the crystallographic struct ures thus reveal a number of subtle but consistent conformational and surfa ce changes that might serve as markers for differential targeting of protei n-lipid complexes within the cell. Most changes are consistent from ligand to ligand, however there are some ligand-specific changes. Comparable calcu lations with intestinal fatty-acid-binding protein and other vertebrate iLB Ps show differences in the electrostatic topology, hydrophobic topology, an d in localized changes in solvent exposure near the ligand entry portal. Th ese results provide a basis toward understanding the functional and mechani stic differences among these highly structurally homologous proteins. Furth er, they suggest that iLBPs from different tissues exhibit one of two predo minant end-state structural distributions of the ligand entry portal. (C) 1 998 Wiley-Liss, Inc.