Molecular chaperones maximize the native state yield on biological times by driving substrates out of equilibrium
Molecular chaperones maximize the native state yield on biological times by driving substrates out of equilibrium
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DOI：
10.1073/pnas.1712962114
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发表时间：
2017-12-19
影响因子：
11.1
通讯作者：
Thirumalai, D.
中科院分区：
文献类型：
--
作者：
Chakrabarti, Shaon;Hyeon, Changbong;Thirumalai, D.
分子伴侣促进蛋白质和RNA在体内的折叠。在生理条件下，四膜虫核酶被RNA分子伴侣CyT-19体外折叠的行为是矛盾的；增加分子伴侣的浓度会减少天然核酶的产量。相比之下，蛋白质伴侣GroEL的工作方式与预期不谋而合；天然底物的产量随着伴侣浓度的增加而增加。因此，不同的伴侣辅助核酶折叠与它作为高效退火机的预期相矛盾。为了解决这一悖论，我们提出了一个基于迭代退火机制(IAM)的最小随机模型，该模型统一描述了伴侣介导的蛋白质和RNA折叠。我们的理论提供了一个一般关系，它定量地预测了自然态的产额如何依赖于伴侣浓度。虽然四膜虫核酶中天然状态的绝对产率降低，但折叠速度和稳态天然产量的乘积在这两种情况下都增加了。通过利用ATP水解产生的能量，CyT-19和GroEL都使其底物浓度远远超出平衡，从而在短时间内使天然产量最大化。当底物浓度超过GroEL时，这也是成立的。我们的发现满足了这样的预期，即蛋白质和RNA在生物相关的时间尺度上被伴侣折叠，即使最终产量低于平衡热力学所规定的水平。该理论预测，体内伴侣的数量已经进化为在给定时间内优化RNA和蛋白质折叠状态的自然状态生产。
Molecular chaperones facilitate the folding of proteins and RNA in vivo. Under physiological conditions, the in vitro folding of Tetrahymena ribozyme by the RNA chaperone CYT-19 behaves paradoxically; increasing the chaperone concentration reduces the yield of native ribozymes. In contrast, the protein chaperone GroEL works as expected; the yield of the native substrate increases with chaperone concentration. The discrepant chaperone-assisted ribozyme folding thus contradicts the expectation that it operates as an efficient annealing machine. To resolve this paradox, we propose a minimal stochastic model based on the Iterative Annealing Mechanism (IAM) that offers a unified description of chaperone-mediated folding of both proteins and RNA. Our theory provides a general relation that quantitatively predicts how the yield of native states depends on chaperone concentration. Although the absolute yield of native states decreases in the Tetrahymena ribozyme, the product of the folding rate and the steady-state native yield increases in both cases. By using energy from ATP hydrolysis, both CYT-19 and GroEL drive their substrate concentrations far out of equilibrium, thus maximizing the native yield in a short time. This also holds when the substrate concentration exceeds that of GroEL. Our findings satisfy the expectation that proteins and RNA be folded by chaperones on biologically relevant time scales, even if the final yield is lower than what equilibrium thermodynamics would dictate. The theory predicts that the quantity of chaperones in vivo has evolved to optimize native state production of the folded states of RNA and proteins in a given time.