Hsp90 shapes protein and RNA evolution to balance trade-offs between protein stability and aggregation.
Hsp90 shapes protein and RNA evolution to balance trade-offs between protein stability and aggregation.
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DOI：
10.1038/s41467-018-04203-x
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发表时间：
2018-05-03
影响因子：
16.6
通讯作者：
Frydman J
中科院分区：
文献类型：
--
作者：
Geller R;Pechmann S;Acevedo A;Andino R;Frydman J
突变的获得是进化的核心;然而，大多数突变对蛋白质折叠和稳定性的不利影响限制了蛋白质的可进化性。分子伴侣，抑制聚集和促进多肽折叠，可以减轻不稳定突变的影响，从而促进序列多样化。为了阐明分子伴侣如何影响蛋白质进化，我们研究了分子伴侣Hsp 90活性降低对脊髓灰质炎病毒进化的影响。我们发现，热休克蛋白90抵消蛋白质的稳定性和聚集之间的进化权衡。较低的伴侣蛋白水平有利于疏水性和蛋白质聚集倾向降低的变体，但以蛋白质稳定性为代价。值得注意的是，降低Hsp 90活性还促进了结构域间边界处密码子去优化的同义突变簇，可能促进共翻译结构域折叠。我们的研究结果揭示了分子伴侣如何在蛋白质和RNA水平上塑造序列景观，以协调蛋白质稳定性，聚集倾向和翻译速率对成功的蛋白质生物合成的竞争约束。对于伴侣蛋白是否以及如何控制蛋白质进化仍然知之甚少。在这里，作者展示了伴侣Hsp 90如何在多肽和RNA水平上塑造其客户脊髓灰质炎病毒蛋白P1的序列空间，以平衡蛋白质稳定性，聚集和翻译速率之间的进化权衡。
Acquisition of mutations is central to evolution; however, the detrimental effects of most mutations on protein folding and stability limit protein evolvability. Molecular chaperones, which suppress aggregation and facilitate polypeptide folding, may alleviate the effects of destabilizing mutations thus promoting sequence diversification. To illuminate how chaperones can influence protein evolution, we examined the effect of reduced activity of the chaperone Hsp90 on poliovirus evolution. We find that Hsp90 offsets evolutionary trade-offs between protein stability and aggregation. Lower chaperone levels favor variants of reduced hydrophobicity and protein aggregation propensity but at a cost to protein stability. Notably, reducing Hsp90 activity also promotes clusters of codon-deoptimized synonymous mutations at inter-domain boundaries, likely to facilitate cotranslational domain folding. Our results reveal how a chaperone can shape the sequence landscape at both the protein and RNA levels to harmonize competing constraints posed by protein stability, aggregation propensity, and translation rate on successful protein biogenesis. It remains poorly understood whether and how chaperones control protein evolution. Here the authors show how the chaperone Hsp90 shapes the sequence space of its client, poliovirus protein P1, at the polypeptide and RNA level to balance the evolutionary trade-offs between protein stability, aggregation and translation rate.
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影响因子：
10.5
作者：
Geller, Ron;Vignuzzi, Marco;Frydman, Judith
通讯作者：
Frydman, Judith
影响因子：
2.9
作者：
Bogumil, David;Dagan, Tal
通讯作者：
Dagan, Tal
DOI：
10.1073/pnas.1208138109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Han, Yan;David, Alexandre;Qian, Shu-Bing
通讯作者：
Qian, Shu-Bing
影响因子：
3.7
作者：
Geller R;Andino R;Frydman J
通讯作者：
Frydman J
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y