哺乳动物伴侣蛋白 TRiC/CCT 的 4.0-A 分辨率冷冻电镜结构揭示了其独特的亚基排列。

4.0-A resolution cryo-EM structure of the mammalian chaperonin TRiC/CCT reveals its unique subunit arrangement.

机构信息

National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemsitry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030.

出版信息

Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4967-72. doi: 10.1073/pnas.0913774107. Epub 2010 Mar 1.

Abstract

The essential double-ring eukaryotic chaperonin TRiC/CCT (TCP1-ring complex or chaperonin containing TCP1) assists the folding of approximately 5-10% of the cellular proteome. Many TRiC substrates cannot be folded by other chaperonins from prokaryotes or archaea. These unique folding properties are likely linked to TRiC's unique heterooligomeric subunit organization, whereby each ring consists of eight different paralogous subunits in an arrangement that remains uncertain. Using single particle cryo-EM without imposing symmetry, we determined the mammalian TRiC structure at 4.7-A resolution. This revealed the existence of a 2-fold axis between its two rings resulting in two homotypic subunit interactions across the rings. A subsequent 2-fold symmetrized map yielded a 4.0-A resolution structure that evinces the densities of a large fraction of side chains, loops, and insertions. These features permitted unambiguous identification of all eight individual subunits, despite their sequence similarity. Independent biochemical near-neighbor analysis supports our cryo-EM derived TRiC subunit arrangement. We obtained a Calpha backbone model for each subunit from an initial homology model refined against the cryo-EM density. A subsequently optimized atomic model for a subunit showed approximately 95% of the main chain dihedral angles in the allowable regions of the Ramachandran plot. The determination of the TRiC subunit arrangement opens the way to understand its unique function and mechanism. In particular, an unevenly distributed positively charged wall lining the closed folding chamber of TRiC differs strikingly from that of prokaryotic and archaeal chaperonins. These interior surface chemical properties likely play an important role in TRiC's cellular substrate specificity.

摘要

真核生物双环伴侣蛋白 TRiC/CCT(TCP1-环复合物或含 TCP1 的伴侣蛋白)协助折叠大约 5-10%的细胞蛋白质组。许多 TRiC 底物不能被原核生物或古菌的其他伴侣蛋白折叠。这些独特的折叠特性可能与 TRiC 独特的异源寡聚亚基组织有关,其中每个环由八个不同的同源 paralogous 亚基组成,其排列仍不确定。使用不施加对称性的单颗粒冷冻电镜,我们在 4.7-A 分辨率下确定了哺乳动物 TRiC 的结构。这揭示了其两个环之间存在 2 倍轴,导致环之间存在两个同源亚基相互作用。随后进行的 2 倍对称化映射产生了一个 4.0-A 分辨率的结构,显示出大量侧链、环和插入物的密度。尽管这些特征的序列相似性,这些特征允许明确识别所有八个单独的亚基。独立的生化近邻分析支持我们从冷冻电镜中得出的 TRiC 亚基排列。我们从最初针对冷冻电镜密度进行同源建模的 refine 中为每个亚基获得了 Calpha 骨架模型。随后对亚基的优化原子模型显示,大约 95%的主链二面角处于 Ramachandran 图的允许区域内。TRiC 亚基排列的确定为理解其独特的功能和机制开辟了道路。特别是,TRiC 封闭折叠腔的内壁不均匀分布的带正电荷的壁与原核生物和古菌伴侣蛋白明显不同。这些内部表面化学性质可能在 TRiC 的细胞底物特异性中发挥重要作用。

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