Warwicker Jim, Charonis Spyros, Curtis Robin A
Faculty of Life Sciences, Manchester Institute of Biotechnology , 131 Princess Street, Manchester M1 7DN, U.K.
Mol Pharm. 2014 Jan 6;11(1):294-303. doi: 10.1021/mp4004749. Epub 2013 Nov 27.
Prediction and engineering of protein solubility is an important but imprecise area. While some features are routinely used, such as the avoidance of extensive non-polar surface area, scope remains for benchmarking of sequence and structural features with experimental data. We study properties in the context of experimental solubilities, protein gene expression levels, and families of abundant proteins (serum albumin and myoglobin) and their less abundant paralogues. A common feature that emerges for proteins with elevated solubility and at higher expression and abundance levels is an increased ratio of lysine content to arginine content. We suggest that the same properties of arginine that give rise to its recorded propensity for specific interaction surfaces also lead to favorable interactions at nonspecific contacts, and thus lysine is favored for proteins at relatively high concentration. A survey of protein therapeutics shows that a significant subset possesses a relatively low lysine to arginine ratio, and therefore may not be favored for high protein concentration. We conclude that modulation of lysine and arginine content could prove a useful and relatively simple addition to the toolkit available for engineering protein solubility in biotechnological applications.
蛋白质溶解度的预测与工程是一个重要但并不精确的领域。虽然一些特征经常被使用，比如避免出现大面积的非极性表面积，但利用实验数据对序列和结构特征进行基准测试仍有空间。我们在实验溶解度、蛋白质基因表达水平以及丰富蛋白质家族（血清白蛋白和肌红蛋白）及其低丰度旁系同源物的背景下研究相关特性。溶解度升高、表达和丰度水平较高的蛋白质所呈现出的一个共同特征是赖氨酸含量与精氨酸含量的比值增加。我们认为，精氨酸因其在特定相互作用表面所记录的倾向而具有的相同特性，也会在非特异性接触中产生有利的相互作用，因此对于相对高浓度的蛋白质而言，赖氨酸更受青睐。对蛋白质疗法的一项调查表明，相当一部分蛋白质的赖氨酸与精氨酸比值相对较低，因此可能不利于高蛋白质浓度的情况。我们得出结论，在生物技术应用中，调节赖氨酸和精氨酸含量可能是一种有用且相对简单的方法，可补充到用于工程化蛋白质溶解度的工具包中。
