Cuevas André R, Tillman Matthew C, Wang Meng C, Ortlund Eric A
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA.
Protein Sci. 2025 Jan;34(1):e5249. doi: 10.1002/pro.5249.
Intracellular lipid binding proteins (iLBPs) play crucial roles in lipid transport and cellular metabolism across the animal kingdom. Recently, a fat-to-neuron axis was described in Caenorhabditis elegans, in which lysosomal activity in the fat liberates polyunsaturated fatty acids (PUFAs) that signal to neurons and extend lifespan with durable fecundity. In this study, we investigate the structure and binding mechanisms of a lifespan-extending lipid chaperone, lipid binding protein-3 (LBP-3), which shuttles dihomo-γ-linolenic (DGLA) acid from intestinal fat to neurons. We present the first high-resolution crystal structure of LBP-3, which reveals a classic iLBP fold with an unexpected and unique homodimeric arrangement via interstrand interactions that is incompatible with ligand binding. We identify key ionic interactions that mediate DGLA binding within the lipid binding pocket. Molecular dynamics simulations further elucidate LBP-3's preferential binding to DGLA due to its rotational freedom and access to favorable binding conformations compared to other 20-carbon PUFAs. We also propose that LBP-3 dimerization may be a unique regulatory mechanism for lipid chaperones.
细胞内脂质结合蛋白（iLBPs）在整个动物界的脂质运输和细胞代谢中发挥着关键作用。最近，在秀丽隐杆线虫中描述了一条从脂肪到神经元的轴，其中脂肪中的溶酶体活性释放出多不饱和脂肪酸（PUFAs），这些脂肪酸向神经元发出信号并延长寿命，同时保持持久的繁殖力。在本研究中，我们研究了一种延长寿命的脂质伴侣蛋白——脂质结合蛋白-3（LBP-3）的结构和结合机制，该蛋白将二高-γ-亚麻酸（DGLA）从肠道脂肪转运到神经元。我们展示了LBP-3的首个高分辨率晶体结构，该结构揭示了一种经典的iLBP折叠，通过链间相互作用形成了一种意想不到的独特同二聚体排列，这种排列与配体结合不相容。我们确定了在脂质结合口袋中介导DGLA结合的关键离子相互作用。分子动力学模拟进一步阐明了LBP-3对DGLA的优先结合，这是由于与其他20碳PUFAs相比，DGLA具有旋转自由度并能形成有利的结合构象。我们还提出，LBP-3二聚化可能是脂质伴侣蛋白的一种独特调节机制。
