Fatty Acid- and Retinoid-binding Proteins Have Distinct Binding Pockets for the Two Types of Cargo
Fatty Acid- and Retinoid-binding Proteins Have Distinct Binding Pockets for the Two Types of Cargo
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DOI：
10.1074/jbc.m109.022731
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发表时间：
2009-12-18
影响因子：
4.8
通讯作者：
Tucker, Paul A.
中科院分区：
文献类型：
--
作者：
Jordanova, Rositsa;Groves, Matthew R.;Tucker, Paul A.
寄生线虫会导致人类、动物和植物的严重疾病。它们的脂代谢有限，依赖脂结合蛋白从宿主那里获得这些代谢物。已经描述了几个结构新颖的线虫脂结合蛋白家族，包括脂肪酸和类维A酸结合蛋白家族(FAR)。在作为研究寄生线虫模型的秀丽线虫中，已描述了8个线虫Far蛋白。线虫FAR-7的晶体结构是FAR蛋白的第一个结构，它显示出一个新的折叠。它与哺乳动物的脂肪酸结合蛋白有根本的不同，它有两个由表面凹槽连接的配体结合口袋。第一个可以容纳脂肪酸链，而第二个可以容纳更大的维甲酸。除了通过荧光光谱显示脂质结合外，我们还提供证据表明，视黄醇结合在第二口袋底部附近的保守位置受到酪蛋白激酶II磷酸化的正向调节。Far-7：：GFP(绿色荧光蛋白)的表达表明，它定位于头部、皮下合胞和排泄细胞，但这种定位在饥饿条件下发生了变化。综上所述，我们的研究为研究FAR蛋白的脂结合抑制剂提供了基本的结构和功能信息。
Parasitic nematodes cause serious diseases in humans, animals, and plants. They have limited lipid metabolism and are reliant on lipid-binding proteins to acquire these metabolites from their hosts. Several structurally novel families of lipid-binding proteins in nematodes have been described, including the fatty acid- and retinoid-binding protein family (FAR). In Caenorhabditis elegans, used as a model for studying parasitic nematodes, eight C. elegans FAR proteins have been described. The crystal structure of C. elegans FAR-7 is the first structure of a FAR protein, and it exhibits a novel fold. It differs radically from the mammalian fatty acid- binding proteins and has two ligand binding pockets joined by a surface groove. The first can accommodate the aliphatic chain of fatty acids, whereas the second can accommodate the bulkier retinoids. In addition to demonstrating lipid binding by fluorescence spectroscopy, we present evidence that retinol binding is positively regulated by casein kinase II phosphorylation at a conserved site near the bottom of the second pocket. far-7::GFP (green fluorescent protein) expression shows that it is localized in the head hypodermal syncytia and the excretory cell but that this localization changes under starvation conditions. In conclusion, our study provides the basic structural and functional information for investigation of inhibitors of lipid binding by FAR proteins.