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首页> 美国卫生研究院文献>Elsevier Sponsored Documents >Monitoring Copopulated Conformational States During Protein Folding Events Using Electrospray Ionization-Ion Mobility Spectrometry-Mass Spectrometry
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Monitoring Copopulated Conformational States During Protein Folding Events Using Electrospray Ionization-Ion Mobility Spectrometry-Mass Spectrometry

机译：使用电喷雾电离-离子迁移谱-质谱法监测蛋白质折叠过程中共居的构象状态

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The precise mechanism of protein folding remains elusive and there is a deficiency of biophysical techniques that are capable of monitoring the individual behavior of copopulated protein conformers during the folding process. Herein, an ion mobility spectrometry (IMS) device integrated with electrospray ionization mass spectrometry (ESI-MS) has been used to successfully separate and analyze protein conformers differing in cross section and/or charge state. In an initial test, an ensemble of folded and partially folded conformers of the protein cytochrome c was separated. A detailed study undertaken on the amyloidogenic protein β2-microglobulin (β2m), which forms fibrils by protein unfolding followed by self-aggregation and is responsible for the disease dialysis-related amyloidosis, has generated important insights into its folding landscape. Initially, a systematic titration of β2m over the pH range 2 to 7 using ESI-IMS-MS allowed individual conformers to be monitored and quantified throughout the acid denaturation process. Furthermore, a comparison of wild-type β2m with single and double amino acid variants with a range of folding stabilities and propensities for amyloid fibril formation has provided illuminating evidence of the role of different conformers in protein stability and amyloidogenic aggregation. The ESI-IMS-MS data presented here not only demonstrate an important and informative further dimension to ESI-MS, but also illustrate the potential of the ESI-IMS-MS technique for unravelling protein folding enigmas in general and studying protein misfolding diseases in particular.
机译：蛋白质折叠的精确机制仍然难以捉摸，并且缺乏能够在折叠过程中监测共同填充的蛋白质构象异构体行为的生物物理技术。在本文中，与电喷雾电离质谱法（ESI-MS）集成的离子迁移谱法（IMS）装置已被用于成功地分离和分析横截面和/或电荷状态不同的蛋白质构象异构体。在初始测试中，分离了折叠的和部分折叠的蛋白质细胞色素c构象体。对淀粉样蛋白原蛋白β2-微球蛋白（β2m）的详细研究进行了研究，该蛋白通过蛋白质解折叠并随后自聚集形成原纤维，并与疾病透析相关的淀粉样变性有关，对折叠现象产生了重要的见解。最初，使用ESI-IMS-MS在2至7的pH范围内系统地滴定β2m，可以在整个酸变性过程中对各个构象异构体进行监测和定量。此外，将野生型β2m与具有折叠稳定性和淀粉样蛋白原纤维形成倾向的单氨基酸和双氨基酸变体进行比较，提供了不同构象异构体在蛋白质稳定性和淀粉样生成中的作用的有力证据。此处提供的ESI-IMS-MS数据不仅证明了ESI-MS的重要意义和进一步的内容，而且还展示了ESI-IMS-MS技术在一般情况下揭示蛋白质折叠谜团和研究蛋白质错误折叠疾病的潜力。

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