(Almost) Everything in Cotranslational Folding Makes Sense in the Light of Evolution.
(Almost) Everything in Cotranslational Folding Makes Sense in the Light of Evolution.
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（几乎）从进化的角度来看，共平移折叠中的一切都有意义。
DOI：
10.1016/j.bpj.2020.08.007
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发表时间：
2020
影响因子：
3.4
通讯作者：
Ghosh,Kingshuk
中科院分区：
文献类型：
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作者：
Ghosh,Kingshuk
由于安芬森的经典发现，现在很常见的是，通过加入变性剂而展开的“全长”蛋白质序列，可以在稀释变性剂后自发重新折叠。也许不那么主流，尽管一个几乎和安芬森的原始工作一样古老的观察(见(1)中的参考文献)是，在核糖体上翻译的“部分合成的”蛋白质分子也可以开始折叠，尽管是部分折叠。折叠和翻译同时发生的过程称为共翻译折叠(Co-Tf)。翻译后折叠(Post-Tf)是指全长蛋白质合成后的折叠。Post-Tf体现了一个核心概念，即编码在全长初级序列中的“静态信息”决定了折叠和功能。联合组织提出了一种新范式的可能性，即“信息生产”可以影响功能。现在出现了以下问题：联合转铁蛋白和后转铁蛋白最终是否具有相同的生物学目的？最近一系列令人印象深刻的实验和理论工作为这个问题提供了许多见解。首先，多项实验现在已经最终证明，蛋白质可以在翻译过程中开始折叠(1)。实验进一步表明，与变性后的复性相比，Co-Tf可以提高折叠蛋白和功能蛋白的得率。除了设计新的技术外，实验者还巧妙地使用同义突变来改变翻译速度，方法是在保持相同氨基酸序列的情况下插入慢速或快译密码子。总体共识是，翻译速度可以改变，以控制折叠途径/动力学和中间结构的形成，这反过来又影响蛋白质的聚集倾向和活性(3-5)。越来越多的研究支持Co-TF在生物学功能中的重要作用。上面只提到了几个，因为这里的空间有限。蛋白质序列中特定位置的慢翻译密码子在不同物种中被发现是保守的，这暗示了COTF的进化作用。Pl Clark和他的同事们已经证明，改变密码子甚至可以改变细胞的健康状况。综上所述，越来越多的证据表明，蛋白质已经进化到以共翻译方式折叠。然而，这些论点主要是事后的，是从进化的后果中吸取教训的。我们缺乏一个“向前模型”来理解蛋白质序列在Co-Tf下是如何进化的。在本期《生物物理杂志》上，赵、雅各布斯和沙克诺维奇正面接受了这一挑战(7)。他们展示了一个简单而优雅的模型，其中包含了基本的
Thanks to Anfinsen’s classic finding, it is now commonplace that ‘‘full-length’’protein sequences, unfolded by adding denaturant, can spontaneously refold upon diluting out the denaturant. Perhaps less mainstream, although an observation almost as old as Anfinsen’s original work (see references in (1)), is that ‘‘partially synthesized’’protein molecules translated on the ribosome can also begin to fold, albeit partially. The process of folding and translation occurring simultaneously is called cotranslational folding (Co-tf). Post-translational folding (Post-tf) denotes folding of the full-length protein after synthesis. Post-tf embodies the central notion that ‘‘static information’’encoded in the full-length primary sequence dictates fold and function. Co-tf raises the possibility of a new paradigm that ‘‘information production’’can influence function. The following question now arises: do Co-tf and Post-tf ultimately serve the same biological purpose? An impressive array of recent experimental and theoretical efforts provide many insights to this question. First, multiple experiments have now conclusively proven that proteins can begin to fold during translation (1). Experiments have further revealed that Co-tf can increase the yield of folded and functional proteins compared with refolding after denaturation (2). In addition to devising new techniques, experimentalists have cleverly used synonymous mutations to vary the speed of translation by inserting slow or fast-translating codons while maintaining the same amino acid sequence. The overall consensus is that translational speed can be varied to control the folding pathway/kinetics and the formation of intermediate structures, which, in turn, affect the propensity to aggregate and the activity of the protein (3–5).A growing list of studies support the important role of Co-tf in biological function. Only a few were noted above because space here is limited. Slowtranslating codons in specific locations in protein sequences have been found to be conserved across diverse species, hinting at an evolutionary role for Cotf. PL Clark and colleagues have shown that changing codons can even alter cellular fitness (6). Taken together, there is mounting evidence that proteins have evolved to fold cotranslationally. Yet, these arguments are primarily post hoc, learning from the aftermath of evolution. We lack a ‘‘forward model’’to understand how protein sequences evolve under Co-tf. In this issue of Biophysical Journal, Zhao, Jacobs, and Shakhnovich embrace this challenge head on (7). They present a simple yet elegant model incorporating the essential