蛋白质结构。转运蛋白（TSPO）的晶体结构及人类多态性的突变模拟物。
Protein structure. Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism.
作者信息
Li Fei, Liu Jian, Zheng Yi, Garavito R Michael, Ferguson-Miller Shelagh
机构信息
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA.
出版信息
Science. 2015 Jan 30;347(6221):555-8. doi: 10.1126/science.1260590.
Abstract
The 18-kilodalton translocator protein (TSPO), proposed to be a key player in cholesterol transport into mitochondria, is highly expressed in steroidogenic tissues, metastatic cancer, and inflammatory and neurological diseases such as Alzheimer's and Parkinson's. TSPO ligands, including benzodiazepine drugs, are implicated in regulating apoptosis and are extensively used in diagnostic imaging. We report crystal structures (at 1.8, 2.4, and 2.5 angstrom resolution) of TSPO from Rhodobacter sphaeroides and a mutant that mimics the human Ala(147)→Thr(147) polymorphism associated with psychiatric disorders and reduced pregnenolone production. Crystals obtained in the lipidic cubic phase reveal the binding site of an endogenous porphyrin ligand and conformational effects of the mutation. The three crystal structures show the same tightly interacting dimer and provide insights into the controversial physiological role of TSPO and how the mutation affects cholesterol binding.
摘要
18千道尔顿转位蛋白（TSPO）被认为是胆固醇转运至线粒体过程中的关键因子，在类固醇生成组织、转移性癌症以及诸如阿尔茨海默病和帕金森病等炎症性和神经性疾病中高度表达。TSPO配体，包括苯二氮䓬类药物，与细胞凋亡调节有关，并广泛应用于诊断成像。我们报道了来自球形红细菌的TSPO及其一个模拟与精神疾病和孕烯醇酮生成减少相关的人类丙氨酸（147）→苏氨酸（147）多态性的突变体的晶体结构（分辨率分别为1.8、2.4和2.5埃）。在脂质立方相中获得的晶体揭示了内源性卟啉配体的结合位点以及该突变的构象效应。这三种晶体结构显示出相同的紧密相互作用二聚体，并为TSPO存在争议的生理作用以及该突变如何影响胆固醇结合提供了见解。
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本文引用的文献
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Science. 2014 Mar 21;343(6177):1363-6. doi: 10.1126/science.1248725.
2
Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis.转位蛋白/外周苯二氮䓬受体并非类固醇激素生物合成所必需。
Endocrinology. 2014 Jan;155(1):89-97. doi: 10.1210/en.2013-1556. Epub 2013 Dec 20.
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Evolutionary origin of the mitochondrial cholesterol transport machinery reveals a universal mechanism of steroid hormone biosynthesis in animals.线粒体胆固醇转运机制的进化起源揭示了动物甾体激素生物合成的普遍机制。
PLoS One. 2013 Oct 4;8(10):e76701. doi: 10.1371/journal.pone.0076701. eCollection 2013.
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Characterization and modeling of the oligomeric state and ligand binding behavior of purified translocator protein 18 kDa from Rhodobacter sphaeroides.纯化自球形红杆菌的 18kDa 转位蛋白寡聚状态和配体结合行为的表征和建模。
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Bipolar Disorder is associated with the rs6971 polymorphism in the gene encoding 18 kDa Translocator Protein (TSPO).双相情感障碍与编码 18 kDa 转位蛋白（TSPO）的基因中的 rs6971 多态性有关。
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A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation.一个 18 kDa 转位蛋白的遗传多态性影响了人脑中这种神经炎症生物标志物的体外和体内放射性配体结合。
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