Jacob Etai, Horovitz Amnon, Unger Ron
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 52900, Israel.
Bioinformatics. 2007 Jul 1;23(13):i240-8. doi: 10.1093/bioinformatics/btm180.
The folding of many proteins in vivo and in vitro is assisted by molecular chaperones. A well-characterized molecular chaperone system is the chaperonin GroEL/GroES from Escherichia coli which has a homolog found in the eukaryotic cytosol called CCT. All chaperonins have a ring structure with a cavity in which the substrate protein folds. An interesting difference between prokaryotic and eukaryotic chaperonins is in the nature of the ATP-mediated conformational changes that their ring structures undergo during their reaction cycle. Prokaryotic chaperonins are known to exhibit a highly cooperative concerted change of their cavity surface while in eukaryotic chaperonins the change is sequential. Approximately 70% of proteins in eukaryotic cells are multi-domain whereas in prokaryotes single-domain proteins are more common. Thus, it was suggested that the different modes of action of prokaryotic and eukaryotic chaperonins can be explained by the need of eukaryotic chaperonins to facilitate folding of multi-domain proteins.
Using a 2D square lattice model, we generated two large populations of single-domain and double-domain substrate proteins. Chaperonins were modeled as static structures with a cavity wall with which the substrate protein interacts. We simulated both concerted and sequential changes of the cavity surfaces and demonstrated that folding of single-domain proteins benefits from concerted but not sequential changes whereas double-domain proteins benefit also from sequential changes. Thus, our results support the suggestion that the different modes of allosteric switching of prokaryotic and eukaryotic chaperonin rings have functional implications as it enables eukaryotic chaperonins to better assist multi-domain protein folding.
许多蛋白质在体内和体外的折叠都受到分子伴侣的协助。一个特征明确的分子伴侣系统是来自大肠杆菌的伴侣蛋白GroEL/GroES，在真核细胞溶质中发现了它的一个同源物，称为CCT。所有伴侣蛋白都具有环形结构，带有一个供底物蛋白在其中折叠的腔。原核和真核伴侣蛋白之间一个有趣的差异在于其环形结构在反应周期中经历的由ATP介导的构象变化的性质。已知原核伴侣蛋白的腔表面会发生高度协同的一致变化，而真核伴侣蛋白的变化是顺序性的。真核细胞中约70%的蛋白质是多结构域的，而在原核生物中，单结构域蛋白质更为常见。因此，有人提出原核和真核伴侣蛋白不同的作用模式可以通过真核伴侣蛋白促进多结构域蛋白质折叠的需求来解释。
使用二维方格模型，我们生成了大量的单结构域和双结构域底物蛋白群体。伴侣蛋白被建模为具有腔壁的静态结构，底物蛋白与之相互作用。我们模拟了腔表面的协同和顺序变化，证明单结构域蛋白质的折叠受益于协同变化而非顺序变化，而双结构域蛋白质也受益于顺序变化。因此，我们的结果支持了这样的观点，即原核和真核伴侣蛋白环的变构转换不同模式具有功能意义，因为它使真核伴侣蛋白能够更好地协助多结构域蛋白质折叠。
