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Abstract

Members of the fatty acid binding protein (FABP) family function as intracellular transporters of hydrophobic molecules, facilitating both fatty acid and lipid metabolism. FABPs share a common tertiary structure of beta barrel pocket for ligand incorporation with a flexible lid domain. Dysfunction of brain fatty acid binding protein (FABP7) has been associated with a variety of neurological disorders relating to sleep, autism, and schizophrenia. FABPs have been shown to bind small hydrophobic molecules such as fatty acids, endocannabinoids, and phytocannabinoids. Transport of these ligands is mediated through both protein-membrane and protein-protein interactions. FABP7 bares a nuclear localization signal that allows ligand- dependent transport to the nucleus through the nuclear pore complex. Once in the nuclear pore complex, FABP7 can then exchange its cargo with transcription factors. FABP7 can also exchange cargo and interact with cytosolic proteins when its cargo does not result in nuclear localization. It has been suggested that the model for ligand-dependent nuclear localization is mediated by tighter binding interactions with ligands that preferentially translocate FABP7 to the nucleus. FABP7 bound with docosahexaenoic acid results in nuclear localization, however other similar fatty acids such as oleic acid and stearic acid do not. Here a combination of biophysical experimental and computational methods is used to provide a model for the observed ligand- dependent nuclear transportation. We show with NMR experiments and computational simulations that ligand-dependent nuclear localization is associated to specific protein dynamics in the lid domain and not preferential binding to different ligands. Furthermore, we show that a highly dynamic apo protein equilibria and heterogenous ligand conformations make FABP7 ligand binding resistant to mutations. NMR experiments reveal that FABP7 interacts with micelles through the lid domain. Finally profound changes in the lid domain region are observed in biologically relevant T60M mutation of FABP7.