Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure.
Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure.
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DOI：
10.1038/ncomms14893
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发表时间：
2017-03-30
影响因子：
16.6
通讯作者：
Zweckstetter M
中科院分区：
文献类型：
--
作者：
Jaipuria G;Leonov A;Giller K;Vasa SK;Jaremko Ł;Jaremko M;Linser R;Becker S;Zweckstetter M
胆固醇是膜蛋白功能的重要调节剂。然而，这一过程中涉及的确切机制仍然没有完全了解。在这里，我们研究如何的三级和四级结构的线粒体转运蛋白TSPO，结合胆固醇与纳摩尔亲和力，是受这种甾醇。通过固态NMR光谱对TSPO的残基特异性分析揭示了TSPO在膜中的动态单体-二聚体平衡。胆固醇与TSPO的胆固醇识别基序的结合导致整个蛋白质的结构变化，其将动态平衡向转运体单体转移。与变构机制一致，寡聚化界面内的突变干扰位于距离界面35 μ m的跨膜区，达到TSPO的胆固醇结合基序。间插跨膜区的较低结构稳定性为信号传递提供了机制基础。因此，我们的研究揭示了一个变构信号通路，连接膜蛋白的三级和四级结构与胆固醇结合。外线粒体膜转运蛋白（TSPO）介导几种线粒体功能，并以高亲和力结合胆固醇。在这里，作者使用固态NMR来显示胆固醇与TSPO的结合导致调节TSPO寡聚化的变构变化。
Cholesterol is an important regulator of membrane protein function. However, the exact mechanisms involved in this process are still not fully understood. Here we study how the tertiary and quaternary structure of the mitochondrial translocator protein TSPO, which binds cholesterol with nanomolar affinity, is affected by this sterol. Residue-specific analysis of TSPO by solid-state NMR spectroscopy reveals a dynamic monomer–dimer equilibrium of TSPO in the membrane. Binding of cholesterol to TSPO's cholesterol-recognition motif leads to structural changes across the protein that shifts the dynamic equilibrium towards the translocator monomer. Consistent with an allosteric mechanism, a mutation within the oligomerization interface perturbs transmembrane regions located up to 35 Å away from the interface, reaching TSPO's cholesterol-binding motif. The lower structural stability of the intervening transmembrane regions provides a mechanistic basis for signal transmission. Our study thus reveals an allosteric signal pathway that connects membrane protein tertiary and quaternary structure with cholesterol binding. The outer mitochondrial membrane translocator protein (TSPO) mediates several mitochondrial functions and binds cholesterol with a high affinity. Here the authors use solid-state NMR to show that cholesterol binding to TSPO results in allosteric changes that modulate TSPO oligomerization.