Structural characterization of life-extending Caenorhabditis elegans Lipid Binding Protein 8
Structural characterization of life-extending Caenorhabditis elegans Lipid Binding Protein 8
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DOI：
10.1038/s41598-019-46230-8
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发表时间：
2019-07-10
影响因子：
4.6
通讯作者：
Ortlund, Eric A.
中科院分区：
文献类型：
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作者：
Tillman, Matthew C.;Khadka, Manoj;Ortlund, Eric A.
溶酶体在调节寿命方面起着至关重要的作用。溶酶体降解与自噬密切相关，自噬是许多长寿模式所诱导的，也是延长寿命所必需的。溶酶体也是信号转导的中枢，并通过影响核转录来调节寿命。在秀丽隐杆线虫中，溶酶体相关脂肪酸结合蛋白LBP-8介导了一条溶酶体到细胞核的逆行信号通路。LBP-8穿梭溶酶体脂质进入细胞核，激活脂质调节的核受体NHR-49和NHR-80，从而促进寿命。然而，LBP-8作用的结构基础尚不清楚。在这里，我们确定了这种延长寿命的蛋白质LBP-8的第一个1.3埃高分辨率结构，这使我们能够确定结构保守的核定位信号和参与脂质结合的氨基酸。此外，我们描述了LBP-8能够结合的脂肪酸范围，并表明它与蠕虫体内延长寿命的配体（如油酸和油脂乙醇酰胺）具有高亲和力。
The lysosome plays a crucial role in the regulation of longevity. Lysosomal degradation is tightly coupled with autophagy that is induced by many longevity paradigms and required for lifespan extension. The lysosome also serves as a hub for signal transduction and regulates longevity via affecting nuclear transcription. One lysosome-to-nucleus retrograde signaling pathway is mediated by a lysosome-associated fatty acid binding protein LBP-8 in Caenorhabditis elegans. LBP-8 shuttles lysosomal lipids into the nucleus to activate lipid regulated nuclear receptors NHR-49 and NHR-80 and consequently promote longevity. However, the structural basis of LBP-8 action remains unclear. Here, we determined the first 1.3 angstrom high-resolution structure of this life-extending protein LBP-8, which allowed us to identify a structurally conserved nuclear localization signal and amino acids involved in lipid binding. Additionally, we described the range of fatty acids LBP-8 is capable of binding and show that it binds to life-extending ligands in worms such as oleic acid and oleoylethanolamide with high affinity.