Members of the fatty acid binding protein (FABP) family function as intracellular transporters of long chain fatty acids and other hydrophobic molecules to different cellular compartments. Brain fatty acid binding protein (FABP7) exhibits ligand-directed differences in cellular transport behavior. For example, when FABP7 binds to docosahexaenoic acid (DHA), the complex relocates to the nucleus and influences transcriptional activity, whereas FABP7 bound with monosaturated fatty acids remain in the cytosol. We used a variety of biophysical techniques to enhance understanding of ligand-directed transport. Specifically, we examine how FABP7 binds to fatty acids, including saturated stearic acid (SA), monounsaturated oleic acid (OA), and polyunsaturated DHA. We find that at 37°C FABP7 has near equivalent binding affinities for the fatty acids, while at lower temperatures, FABP7 exhibits a preference for the unsaturated fatty acids. Therefore, nuclear localization of the FABP7-DHA complex cannot be explained by binding preferences. Using NMR spectroscopy and molecular dynamics simulations, we observe that DHA uniquely affects the portal region of FABP7, which could enhance the complex’s nuclear localization. Mutations to purported critical binding residues (R126L and Y128F) have little effect on fatty acid binding, with molecular dynamics simulations revealing that the bound fatty acid can adopt binding poses that can accommodate the mutations.

中文翻译：

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脑脂肪酸结合蛋白对脂肪酸表现出非优先和抗突变的结合

脂肪酸结合蛋白 (FABP) 家族的成员充当长链脂肪酸和其他疏水分子到不同细胞区室的细胞内转运蛋白。脑脂肪酸结合蛋白 (FABP7) 在细胞转运行为中表现出配体导向的差异。例如，当 FABP7 与二十二碳六烯酸 (DHA) 结合时，复合物重新定位到细胞核并影响转录活性，而与单饱和脂肪酸结合的 FABP7 则保留在细胞质中。我们使用了多种生物物理技术来增强对配体导向运输的理解。具体来说，我们研究了 FABP7 如何与脂肪酸结合，包括饱和硬脂酸 (SA)、单不饱和油酸 (OA) 和多不饱和 DHA。我们发现在 37°C FABP7 对脂肪酸的结合亲和力几乎相等，而在较低温度下，FABP7 表现出对不饱和脂肪酸的偏好。因此，FABP7-DHA 复合物的核定位不能用结合偏好来解释。使用核磁共振波谱和分子动力学模拟，我们观察到 DHA 独特地影响 FABP7 的门户区域，这可以增强复合物的核定位。据称关键结合残基（R126L 和 Y128F）的突变对脂肪酸结合几乎没有影响，分子动力学模拟表明结合的脂肪酸可以采用可以适应突变的结合姿势。我们观察到 DHA 独特地影响 FABP7 的门户区域，这可以增强复合物的核定位。据称关键结合残基（R126L 和 Y128F）的突变对脂肪酸结合几乎没有影响，分子动力学模拟表明结合的脂肪酸可以采用可以适应突变的结合姿势。我们观察到 DHA 独特地影响 FABP7 的门户区域，这可以增强复合物的核定位。据称关键结合残基（R126L 和 Y128F）的突变对脂肪酸结合几乎没有影响，分子动力学模拟表明结合的脂肪酸可以采用可以适应突变的结合姿势。