A Free Energy Barrier Caused by the Refolding of an Oligomeric Intermediate Controls the Lag Time of Amyloid Formation by hIAPP.
A Free Energy Barrier Caused by the Refolding of an Oligomeric Intermediate Controls the Lag Time of Amyloid Formation by hIAPP.
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DOI：
10.1021/jacs.7b08830
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发表时间：
2017-11-22
影响因子：
15
通讯作者：
Zanni MT
中科院分区：
文献类型：
--
作者：
Serrano AL;Lomont JP;Tu LH;Raleigh DP;Zanni MT
在形成淀粉样蛋白原纤维的过程中形成的短暂聚集的寡聚体可能构成与许多淀粉样蛋白相关疾病相关的毒性最大的聚集体。大多数用于描述淀粉样蛋白聚集的成核理论预测低低聚物浓度，并且不考虑可能与低聚物和纤维状态之间的结构重排相关的自由能成本。我们已经使用同位素标记和二维红外光谱法来光谱解析与II型糖尿病相关的人胰岛淀粉样蛋白（hIAPP或胰淀素）聚集过程中的低聚中间体。结构重排包括hIAPP的F23 G24 A25 I26 L27区域，其从无规卷曲结构开始，演变成包含至少5条链的有序β-折叠寡聚体，然后在原纤维结构中部分紊乱。测得的超临界浓度在150和250 μM之间，这是设定低聚物自由能的热力学参数。三态动力学模型拟合实验数据，但仅当其包括>3 kcal/mol的浓度无关性自由能势垒，其代表将低聚中间体重折叠成淀粉样蛋白原纤维结构的自由能成本;即，需要“低聚物活化”。该屏障在自由能景观中产生过渡态，其减缓原纤维形成并在滞后期期间产生稳定的低聚物群体，甚至在低于超临界浓度的浓度下。目前的动力学模型中缺少结构和动力学之间的联系。我们的实验和建模提供的证据表明，聚集过程中的蛋白质结构重排影响有毒寡聚物物种的种群和动力学。
Transiently populated oligomers formed en route to amyloid fibrils may constitute the most toxic aggregates associated with many amyloid-associated diseases. Most nucleation theories used to describe amyloid aggregation predict low oligomer concentrations and do not take into account free energy costs that may be associated with structural rearrangements between the oligomer and fiber states. We have used isotope labeling and two-dimensional infrared spectroscopy to spectrally resolve an oligomeric intermediate during the aggregation of the human islet amyloid protein (hIAPP or amylin), the protein associated with type II diabetes. A structural rearrangement includes the F23G24A25I26L27 region of hIAPP, which starts from a random coil structure, evolves into ordered β-sheet oligomers containing at least 5 strands, and then partially disorders in the fibril structure. The supercritical concentration is measured to be between 150 and 250 μM, which is the thermodynamic parameter that sets the free energy of the oligomers. A 3-state kinetic model fits the experimental data, but only if it includes a concentration independent free energy barrier >3 kcal/mol that represents the free energy cost of refolding the oligomeric intermediate into the structure of the amyloid fibril; i.e., “oligomer activation” is required. The barrier creates a transition state in the free energy landscape that slows fibril formation and creates a stable population of oligomers during the lag phase, even at concentrations below the supercritical concentration. Largely missing in current kinetic models is a link between structure and kinetics. Our experiments and modeling provide evidence that protein structural rearrangements during aggregation impact the populations and kinetics of toxic oligomeric species.
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影响因子：
3.5
作者：
BETSHOLTZ, C;CHRISTMANSSON, L;WESTERMARK, P
通讯作者：
WESTERMARK, P
影响因子：
3.3
作者：
Andrews, Jennifer M.;Roberts, Christopher J.
通讯作者：
Roberts, Christopher J.
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
--
作者：
Auer, Stefan;Dobson, Christopher M.;Vendruscolo, Michele
通讯作者：
Vendruscolo, Michele
DOI：
10.1021/acs.jpcb.5b07706
发表时间：
2015-11-05
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Dunkelberger EB;Grechko M;Zanni MT
通讯作者：
Zanni MT