Stefani Massimo
Department of Biochemical Sciences and Research Centre on the Molecular Basis of Neurodegeneration (CIMN), University of Florence, Florence, Italy.
Int J Mol Sci. 2008 Dec;9(12):2515-2542. doi: 10.3390/ijms9122515. Epub 2008 Dec 9.
Protein folding, misfolding and aggregation, as well as the way misfolded and aggregated proteins affects cell viability are emerging as key themes in molecular and structural biology and in molecular medicine. Recent advances in the knowledge of the biophysical basis of protein folding have led to propose the energy landscape theory which provides a consistent framework to better understand how a protein folds rapidly and efficiently to the compact, biologically active structure. The increased knowledge on protein folding has highlighted its strict relation to protein misfolding and aggregation, either process being in close competition with the other, both relying on the same physicochemical basis. The theory has also provided information to better understand the structural and environmental factors affecting protein folding resulting in protein misfolding and aggregation into ordered or disordered polymeric assemblies. Among these, particular importance is given to the effects of surfaces. The latter, in some cases make possible rapid and efficient protein folding but most often recruit proteins/peptides increasing their local concentration thus favouring misfolding and accelerating the rate of nucleation. It is also emerging that surfaces can modify the path of protein misfolding and aggregation generating oligomers and polymers structurally different from those arising in the bulk solution and endowed with different physical properties and cytotoxicities.
蛋白质折叠、错误折叠和聚集，以及错误折叠和聚集的蛋白质影响细胞活力的方式，正成为分子与结构生物学以及分子医学中的关键主题。蛋白质折叠生物物理基础知识的最新进展促使人们提出了能量景观理论，该理论提供了一个连贯的框架，能更好地理解蛋白质如何快速有效地折叠成紧凑的生物活性结构。对蛋白质折叠的更多了解凸显了其与蛋白质错误折叠和聚集的紧密关系，这两个过程相互竞争激烈，且都基于相同的物理化学基础。该理论还为更好地理解影响蛋白质折叠导致其错误折叠并聚集成有序或无序聚合物聚集体的结构和环境因素提供了信息。其中，表面的影响尤为重要。在某些情况下，表面能使蛋白质快速有效地折叠，但大多数情况下会募集蛋白质/肽，增加其局部浓度，从而有利于错误折叠并加速成核速率。越来越明显的是，表面可以改变蛋白质错误折叠和聚集的途径，生成与本体溶液中产生的结构不同、具有不同物理性质和细胞毒性的寡聚体和聚合物。
