Protein fibrillation lag times during kinetic inhibition.
Protein fibrillation lag times during kinetic inhibition.
复制标题
动力学抑制期间蛋白质原纤维颤动滞后时间。
DOI：
10.1016/j.bpj.2014.06.029
复制
发表时间：
2014
影响因子：
3.4
通讯作者：
J. Caramelo
中科院分区：
文献类型：
--
作者：
Rodrigo S Pagano;Máximo López Medus;Gabriela E. Gómez;P. M. Couto;María S. Labanda;Lucas Landolfo;C. D’Alessio;J. Caramelo
蛋白质聚集与30多种人类病理学有关，包括阿尔茨海默病和帕金森病。由于在原纤化过程开始时形成的小寡聚体可能是毒性最大的元素，因此涉及原纤断裂的治疗策略可能是有害的。另一种称为动力学抑制的方法旨在通过使用稳定亲本蛋白的小配体来防止原纤维形成。在动力学抑制过程中，支配纤颤滞后时间的因素在很大程度上是未知的，尽管它们对于设计有效的长期治疗很重要。抑制剂结合的物种不太可能被纳入到成熟的纤维的核心，虽然它们的存在可能会改变原纤化过程的动力学。例如，结合于聚合物的物质可充当损害成核过程和/或原纤维生长的封端元件。在这里，我们解决这个问题，通过研究两种天然抑制剂的溶菌酶在中性pH值的原纤化行为的影响。我们分析了一组79原纤化曲线中获得的溶菌酶单独和一组37抑制剂的存在下获得。我们使用在相同实验条件下测量的生物结合常数计算了曲线开始时相关物质的浓度。我们发现，结合的蛋白质种类不影响纤维化发作时间，这主要是由未结合的蛋白质种类的浓度存在于平衡。在该系统中，原纤化动力学和抑制剂亲和力的知识足以预测动力学抑制剂对原纤化滞后时间的影响。此外，我们开发了一种新的方法，以更好地估计纤颤滞后时间从实验曲线。
Protein aggregation is linked to more than 30 human pathologies, including Alzheimer's and Parkinson's diseases. Since small oligomers that form at the beginning of the fibrillation process probably are the most toxic elements, therapeutic strategies involving fibril fragmentation could be detrimental. An alternative approach, named kinetic inhibition, aims to prevent fibril formation by using small ligands that stabilize the parent protein. The factors that govern fibrillation lag times during kinetic inhibition are largely unknown, notwithstanding their importance for designing effective long-term therapies. Inhibitor-bound species are not likely to be incorporated into the core of mature fibrils, although their presence could alter the kinetics of the fibrillation process. For instance, inhibitor-bound species may act as capping elements that impair the nucleation process and/or fibril growth. Here, we address this issue by studying the effect of two natural inhibitors on the fibrillation behavior of lysozyme at neutral pH. We analyzed a set of 79 fibrillation curves obtained in lysozyme alone and a set of 37 obtained in the presence of inhibitors. We calculated the concentrations of the relevant species at the beginning of the curves using the inhibitor-binding constants measured under the same experimental conditions. We found that inhibitor-bound protein species do not affect fibrillation onset times, which are mainly determined by the concentration of unbound protein species present in equilibrium. In this system, knowledge of the fibrillation kinetics and inhibitor affinities suffices to predict the effect of kinetic inhibitors on fibrillation lag times. In addition, we developed a new methodology to better estimate fibrillation lag times from experimental curves.
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影响因子：
2.9
作者：
Wiseman,RLuke;Green,NoraS;Kelly,JefferyW
通讯作者：
Kelly,JefferyW
影响因子：
14.8
作者：
Bieschke, Jan;Herbst, Martin;Wanker, Erich E.
通讯作者：
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影响因子：
2.9
作者：
Meng, Fanling;Abedini, Andisheh;Plesner, Annette;Verchere, C. Bruce;Raleigh, Daniel P.
通讯作者：
Raleigh, Daniel P.
DOI：
10.1073/pnas.0400062101
发表时间：
2004-03-02
影响因子：
11.1
作者：
Reixach, N;Deechongkit, S;Buxbaum, JN
通讯作者：
Buxbaum, JN