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Bile salt recognition by human liver fatty acid binding protein

机译：人肝脂肪酸结合蛋白识别胆汁盐

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Fatty acid binding proteins (FABPs) act as intracellular carriers of lipid molecules, and play a role in global metabolism regulation. Liver FABP (L-FABP) is prominent among FABPs for its wide ligand repertoire, which includes long-chain fatty acids as well as bile acids (BAs). In this work, we performed a detailed molecular- and atomic-level analysis of the interactions established by human L-FABP with nine BAs to understand the binding specificity for this important class of cholesterol-derived metabolites. Protein-ligand complex formation was monitored using heteronuclear NMR, steady-state fluorescence spectroscopy, and mass spectrometry. BAs were found to interact with L-FABP with dissociation constants in the narrow range of 0.6-7m; however, the diverse substitution patterns of the sterol nucleus and the presence of side-chain conjugation resulted in complexes endowed with various degrees of conformational heterogeneity. Trihydroxylated BAs formed monomeric complexes in which single ligand molecules occupied similar internal binding sites, based on chemical-shift perturbation data. Analysis of NMR line shapes upon progressive addition of taurocholate indicated that the binding mechanism departed from a simple binary association equilibrium, and instead involved intermediates along the binding path. The co-linear chemical shift behavior observed for L-FABP complexes with cholate derivatives added insight into conformational dynamics in the presence of ligands. The observed spectroscopic features of L-FABP/BA complexes, discussed in relation to ligand chemistry, suggest possible molecular determinants of recognition, with implications regarding intracellular BA transport. Our findings suggest that human L-FABP is a poorly selective, universal BA binder.
机译：脂肪酸结合蛋白（FABP）充当脂质分子的细胞内载体，并在整体代谢调节中发挥作用。肝FABP（L-FABP）在FABP中以其广泛的配体库而著称，其中包括长链脂肪酸和胆汁酸（BAs）。在这项工作中，我们对人L-FABP与9个BA的相互作用进行了详细的分子和原子水平分析，以了解这种重要的胆固醇衍生代谢物的结合特异性。使用异核NMR，稳态荧光光谱和质谱监测蛋白质-配体复合物的形成。发现BAs以0.6-7m的窄范围内的解离常数与L-FABP相互作用。然而，固醇核的不同取代模式和侧链共轭的存在导致复合物具有不同程度的构象异质性。基于化学位移扰动数据，三羟基化的BA形成单体复合物，其中单个配体分子占据相似的内部结合位点。逐步添加牛磺胆酸盐后的NMR线形分析表明，结合机理偏离了简单的二元缔合平衡，而是沿结合路径涉及中间体。 L-FABP配合物与胆酸盐衍生物的共线性化学位移行为增加了对配体存在下构象动力学的了解。有关配体化学的讨论，观察到的L-FABP / BA配合物的光谱特征表明可能的识别分子决定因素，并涉及细胞内BA的运输。我们的发现表明，人L-FABP是选择性差的通用BA结合剂。

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