Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot, 7610001, Israel.
Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, 7610001, Israel.
Small. 2024 May;20(22):e2308069. doi: 10.1002/smll.202308069. Epub 2023 Dec 26.
A notable feature of complex cellular environments is protein-rich compartments that are formed via liquid-liquid phase separation. Recent studies have shown that these biomolecular condensates can play both promoting and inhibitory roles in fibrillar protein self-assembly, a process that is linked to Alzheimer's, Parkinson's, Huntington's, and various prion diseases. Yet, the exact regulatory role of these condensates in protein aggregation remains unknown. By employing microfluidics to create artificial protein compartments, the self-assembly behavior of the fibrillar protein lysozyme within them can be characterized. It is observed that the volumetric parameters of protein-rich compartments can change the kinetics of protein self-assembly. Depending on the change in compartment parameters, the lysozyme fibrillation process either accelerated or decelerated. Furthermore, the results confirm that the volumetric parameters govern not only the nucleation and growth phases of the fibrillar aggregates but also affect the crosstalk between the protein-rich and protein-poor phases. The appearance of phase-separated compartments in the vicinity of natively folded protein complexes triggers their abrupt percolation into the compartments' core and further accelerates protein aggregation. Overall, the results of the study shed more light on the complex behavior and functions of protein-rich phases and, importantly, on their interaction with the surrounding environment.
复杂细胞环境的一个显著特征是富含蛋白质的隔室，这些隔室通过液-液相分离形成。最近的研究表明，这些生物分子凝聚物在纤维状蛋白自组装中既可以起到促进作用，也可以起到抑制作用，而纤维状蛋白自组装与阿尔茨海默病、帕金森病、亨廷顿病和各种朊病毒病有关。然而，这些凝聚物在蛋白质聚集中的确切调节作用仍不清楚。通过采用微流控技术来创建人工蛋白质隔室，可以对其中的纤维状蛋白溶菌酶的自组装行为进行表征。研究发现，富含蛋白质的隔室的体积参数可以改变蛋白质自组装的动力学。根据隔室参数的变化，溶菌酶的纤维化过程要么加速，要么减速。此外，结果证实，体积参数不仅控制纤维状聚集体的成核和生长阶段，还影响富含蛋白质和蛋白质贫乏相之间的串扰。天然折叠蛋白复合物附近出现相分离隔室会触发它们突然渗透到隔室的核心，并进一步加速蛋白质聚集。总的来说，该研究结果更深入地了解了富含蛋白质相的复杂行为和功能，重要的是，还了解了它们与周围环境的相互作用。
