Solution Structure and Backbone Dynamics of Human Liver Fatty Acid Binding Protein: Fatty Acid Binding Revisited
Solution Structure and Backbone Dynamics of Human Liver Fatty Acid Binding Protein: Fatty Acid Binding Revisited
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DOI：
10.1016/j.bpj.2012.04.039
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发表时间：
2012-06-06
影响因子：
3.4
通讯作者：
Hamilton, James A.
中科院分区：
文献类型：
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作者：
Cai, Jun;Luecke, Christian;Hamilton, James A.
肝脂肪酸结合蛋白（Liver fatty acid binding protein, L-FABP）是肝脏中最丰富的一种胞质蛋白，与脂肪酸的细胞内转运、核信号传导和细胞内脂肪分解的调节有关。在细胞内脂质结合蛋白家族的成员中，L-FABP特别令人感兴趣，因为它可以i)同时结合两种脂肪酸分子，ii)容纳各种体积较大的生理配体，如胆红素和脂肪酰基辅酶a。为了更好地了解L-FABP的混杂结合和转运性质，我们利用异核磁共振研究了人类L-FABP结合和不结合配体的结构和动力学。人类L-FABP的整体构象为典型的b-clam基序。根据人类L-FABP/ OA复合物的结构，两个油酸（OA）分子的结合不会实质性地改变蛋白质的构象，但会扰乱参与OA结合的某些主链和侧链质子的化学位移。人类载脂蛋白和全息L-FABP结构的比较显示，没有证据表明大鼠L-FABP在配体结合时具有“开帽”构象或K90侧链的“旋回”机制。相反，我们假设L-FABP中的脂质结合过程与骨干动力学有关。
Liver fatty acid binding protein (L-FABP), a cytosolic protein most abundant in liver, is associated with intracellular transport of fatty acids, nuclear signaling, and regulation of intracellular lipolysis. Among the members of the intracellular lipid binding protein family, L-FABP is of particular interest as it can i), bind two fatty acid molecules simultaneously and ii), accommodate a variety of bulkier physiological ligands such as bilirubin and fatty acyl CoA. To better understand the promiscuous binding and transport properties of L-FABP, we investigated structure and dynamics of human L-FABP with and without bound ligands by means of heteronuclear NMR. The overall conformation of human L-FABP shows the typical b-clam motif. Binding of two oleic acid (OA) molecules does not alter the protein conformation substantially, but perturbs the chemical shift of certain backbone and side-chain protons that are involved in OA binding according to the structure of the human L-FABP/ OA complex. Comparison of the human apo and holo L-FABP structures revealed no evidence for an "open-cap" conformation or a "swivel-back" mechanism of the K90 side chain upon ligand binding, as proposed for rat L-FABP. Instead, we postulate that the lipid binding process in L-FABP is associated with backbone dynamics.