Fatty Acid and Retinol-Binding Protein: Unusual Protein Conformational and Cavity Changes Dictated by Ligand Fluctuations
Fatty Acid and Retinol-Binding Protein: Unusual Protein Conformational and Cavity Changes Dictated by Ligand Fluctuations
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DOI：
10.1021/acs.jcim.9b00364
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发表时间：
2019-08-01
影响因子：
5.6
通讯作者：
Fernandez-Alberti, S.
中科院分区：
文献类型：
--
作者：
Barletta, G. P.;Franchini, G.;Fernandez-Alberti, S.
脂质结合蛋白（LBP）是可溶性蛋白质，负责细胞环境中大量疏水亲脂分子（包括脂肪酸、类固醇和其他脂质）的摄取、转运和储存。在LBP中，脂肪酸结合蛋白（FABPs）对长链脂肪酸具有优先结合亲和力。虽然脊椎动物和无脊椎动物中的大多数FABP呈现类似的β-桶结构，配体容纳在它们的中央腔中，但寄生蠕虫表现出额外的不寻常的富含α-螺旋的脂肪酸和视黄醇结合蛋白（FAR）。在这里，我们报告的扩展分子动力学（MD）模拟的无配体和棕榈酸键状态的美洲钩虫FAR-1（Na-FAR-1）相对于其他经典的β-桶FABP进行比较。主成分分析（PCA）已被用来确定不同的构象通过每个系统在MD模拟。α-螺旋折叠包含一个复杂的内部配体结合腔，具有显着的构象可塑性，允许在holo-Na-FAR-1的不同状态之间可逆切换。由于蛋白质-配体复合物的构象变化，空腔可以改变其大小的三分之一。此外，空腔内的配体不是固定的，而是在弯曲和拉伸构象之间经历大的构象变化。配体构象的这些变化遵循由瞬时蛋白质构象决定的空腔大小的变化。相反，β-桶FABP中的蛋白质-配体复合物围绕独特的构象波动。明显更灵活的holo-Na-FAR-1配体腔解释了其相对于β-桶FABP的更大的配体多重性。
Lipid-binding proteins (LBPs) are soluble proteins responsible for the uptake, transport, and storage of a large variety of hydrophobic lipophilic molecules including fatty acids, steroids, and other lipids in the cellular environment. Among the LBPs, fatty acid binding proteins (FABPs) present preferential binding affinities for long-chain fatty acids. While most of FABPs in vertebrates and invertebrates present similar beta-barrel structures with ligands accommodated in their central cavity, parasitic nematode worms exhibit additional unusual a-helix rich fatty acid- and retinol-binding proteins (FAR). Herein, we report the comparison of extended molecular dynamics (MD) simulations performed on the ligand-free and palmitic acid-bond states of the Necator americanus FAR-1 (Na-FAR-1) with respect to other classical beta-barrel FABPs. Principal component analysis (PCA) has been used to identify the different conformations adopted by each system during MD simulations. The alpha-helix fold encompasses a complex internal ligand-binding cavity with a remarkable conformational plasticity that allows reversible switching between distinct states in the holo-Na-FAR-1. The cavity can change up to one-third of its size affected by conformational changes of the protein-ligand complex Besides, the ligand inside the cavity is not fixed but experiences large conformational changes between bent and stretched conformations. These changes in the ligand conformation follow changes in the cavity size dictated by the transient protein conformation. On the contrary, protein-ligand complex in beta-barrel FABPs fluctuates around a unique conformation. The significantly more flexible holo-Na-FAR-1 ligand-cavity explains its larger ligand multiplicity respect to beta-barrel FABPs.