Department of Pharmacology, University of California, Davis, California, USA.
Biophys J. 2010 Apr 21;98(8):1641-8. doi: 10.1016/j.bpj.2009.12.4295.
This study suggests a molecular mechanism that explains the accumulation of denaturated proinsulin in the endoplasmic reticulum (ER) of beta-cells. Such states were frequently observed in beta-cells experiencing increased demand for insulin production and were shown to lead to secretory dysfunction and diabetes. Here, a self-consistent kinetic model is used to investigate changes in protein translation due to ER overloading. The model is based on a molecular theory that relates the molecular composition and level of molecular crowding in the ER to the kinetic rates of protein folding/misfolding and transit to the Golgi apparatus (GA). This study suggests that molecular crowding forces can increase protein misfolding and impair the transport to the GA, thus overwhelming the quality control mechanism in the ER. A continual accumulation of toxic residues in the ER enhances even further the molecular crowding, accelerating protein denaturation. This article shows that molecular crowding affects differently the transit of various proteins through the ER. Apparently, the molecular crowding level that can inhibit the transport of native proinsulin to the GA influences to a lesser extent the transit of proamylin, a much smaller peptide cosynthesized with proinsulin in the ER. Smaller-volume misfolded proinsulin species may also win the passage competition through the ER and move on the secretory track. However, misfolded proinsulin fails the conversion to active insulin. This study can help us to decipher circumstances leading to the alteration of the secretory function in susceptible beta-cells and the onset of diabetes.
本研究提出了一个分子机制，解释了变性胰岛素原在β细胞内质网（ER）中的积累。这种状态在β细胞经历胰岛素产生需求增加时经常观察到，并且被证明导致分泌功能障碍和糖尿病。在这里，使用自洽的动力学模型来研究由于 ER 过载导致的蛋白质翻译变化。该模型基于一种分子理论，该理论将 ER 中的分子组成和分子拥挤程度与蛋白质折叠/错误折叠和向高尔基体（GA）转运的动力学速率联系起来。本研究表明，分子拥挤力可以增加蛋白质错误折叠并损害向 GA 的转运，从而使 ER 中的质量控制机制不堪重负。在 ER 中有毒残基的持续积累进一步增强了分子拥挤，加速了蛋白质变性。本文表明，分子拥挤以不同的方式影响各种蛋白质通过 ER 的转运。显然，抑制天然胰岛素原向 GA 转运的分子拥挤水平对在 ER 中与胰岛素原共同合成的较小肽原淀粉的转运影响较小。较小体积的错误折叠的胰岛素原物种也可能通过 ER 赢得通过竞争并进入分泌途径。然而，错误折叠的胰岛素原无法转化为活性胰岛素。本研究可以帮助我们破译导致易感β细胞分泌功能改变和糖尿病发病的情况。
