The ligand-mediated affinity of brain-type fatty acid-binding protein for membranes determines the directionality of lipophilic cargo transport |
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| Institution: | 1. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia;2. Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia;3. Western Australian Neuroscience Research Institute, Nedlands, Australia;4. School of Heath Sciences, The University Notre Dame, Fremantle, Western Australia, Australia;5. Experimental and Regenerative Neurosciences, Western Australia, Australia;6. School of Anatomy, Physiology and Human Biology, The University of Western Australia, Nedlands, Australia;7. School of Animal Biology, The University of Western Australia, Nedlands, Australia;1. Institute of Medical Psychology, Goethe University, 60528 Frankfurt am Main, Germany;2. Department of Neurology, Goethe University, 60528 Frankfurt am Main, Germany;3. Max Planck Institute for Empirical Aesthetics, 60322 Frankfurt am Main, Germany;1. Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India;2. Academy of Scientific and Innovative Research, New Delhi, 110025, India;3. Centre of Biomedical Research (CBMR), Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raibareli Road, Lucknow 226014, Uttar Pradesh, India |
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| Abstract: | The intracellular transport of lipophilic cargoes is a highly dynamic process. In eukaryotic cells, the uptake and release of long-chain fatty acids (LCFAs) are executed by fatty-acid binding proteins. However, how these carriers control the directionality of cargo trafficking remains unclear. Here, we revealed that the unliganded archetypal Drosophila brain-type fatty acid-binding protein (dFABP) possesses a stronger binding affinity than its liganded counterpart for empty nanodiscs (ND). Titrating unliganded dFABP and nanodiscs with LCFAs rescued the broadening of FABP cross-peak intensities in HSQC spectra from a weakened protein–membrane interaction. Two out of the 3 strongest LCFA contacting residues in dFABP identified by NMR HSQC chemical shift perturbation (CSP) are also part of the 30 ND-contacting residues (out of the total 130 residues in dFABP), revealed by attenuated TROSY signal in the presence of lipid ND to apo-like dFABP. Our crystallographic temperature factor data suggest enhanced αII helix dynamics upon LCFA binding, compensating for the entropic loss in the βC-D/βE-F loops. The aliphatic tail of bound LCFA impedes the charge-charge interaction between dFABP and the head groups of the membrane, and dFABP is prone to dissociate from the membrane upon ligand binding. We therefore conclude that lipophilic ligands participate directly in the control of the functionally required membrane association and dissociation of FABPs. |
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