Metastable intermediate during hIAPP aggregation catalyzed by membranes as detected with 2D IR spectroscopy.
Metastable intermediate during hIAPP aggregation catalyzed by membranes as detected with 2D IR spectroscopy.
复制标题
用2D IR光谱检测到的膜催化HIAPP聚集期间的中间体。
DOI：
10.1039/d2cb00028h
复制
发表时间：
2022-07-06
影响因子：
4.1
通讯作者：
Zanni, Martin T.
中科院分区：
文献类型：
--
作者：
Dicke, Sidney S.;Maj, Michal;Fields, Caitlyn R.;Zanni, Martin T.
人胰岛淀粉样多肽（hIAPP）聚集成淀粉样纤维涉及寡聚中间体的形成，这些寡聚中间体被认为是导致2型糖尿病中β细胞功能障碍的细胞毒性物质。hIAPP寡聚体渗透或破坏细胞膜可能是一种毒性机制，因此测量在有膜存在时聚集的结构动力学非常有意义。在这项研究中，我们使用二维红外光谱和\(^{13}C^{18}O\)同位素标记来研究在溶液中以及在磷脂囊泡存在下，在L12A13、L16V17、G24A25和V32G33位点形成的寡聚中间体的二级结构。成对的标记监测相关多肽之间的耦合以及相邻残基之间的二面角。在溶液中，L12A13残基除了形成α - 螺旋外还形成寡聚β - 片层，而在磷脂囊泡存在时，它们在整个聚集过程中都是α - 螺旋。在溶液中和在二油酰磷脂酰胆碱（DOPC）囊泡中，L16V17和V32G33在纤维形成之前都具有无序结构。同样，在这两种条件下，G24A25都表现出三态动力学，由具有明确β - 片层结构的寡聚中间体产生。淀粉样纤维的形成通常被认为涉及数量极少且难以通过实验检测的中间体。这些实验证实，当由膜催化时，hIAPP的淀粉样纤维形成包括一种亚稳态中间体，并且该中间体在FGAIL区域的G24A25处具有与溶液中相应中间体相似的结构，该溶液中的中间体被认为是有毒物质。
二维红外光谱和\(^{13}C^{18}O\)同位素标记证实，当由膜催化时，hIAPP的淀粉样形成包括一种亚稳态中间体，该中间体在FGAIL区域的G24A25处具有与溶液中相应中间体相似的结构。
The aggregation of human islet amyloid polypeptide (hIAPP) into amyloid fibrils involves formation of oligomeric intermediates that are thought to be the cytotoxic species responsible for β-cell dysfunction in type 2 diabetes. hIAPP oligomers permeating or disrupting the cellular membrane may be one mechanism of toxicity and so measuring the structural kinetics of aggregation in the presence of membranes is of much interest. In this study, we use 2D IR spectroscopy and 13C18O isotope labeling to study the secondary structure of the oligomeric intermediates formed in solution and in the presence of phospholipid vesicles at sites L12A13, L16V17, G24A25 and V32G33. Pairs of labels monitor the couplings between associated polypeptides and the dihedral angles between adjacent residues. In solution, the L12A13 residues form an oligomeric β-sheet in addition to an α-helix whereas with the phospholipid vesicles they are α-helical throughout the aggregation process. In both solution and with DOPC vesicles, L16V17 and V32G33 have disordered structures until fibrils are formed. Similarly, under both conditions, G24A25 exhibits 3-state kinetics, created by an oligomeric intermediate with a well-defined β-sheet structure. Amyloid fibril formation is often thought to involve intermediates with exceedingly low populations that are difficult to detect experimentally. These experiments establish that amyloid fibril formation of hIAPP when catalyzed by membranes includes a metastable intermediate and that this intermediate has a similar structure at G24A25 in the FGAIL region as the corresponding intermediate in solution, thought to be the toxic species. 2D IR and 13C18O isotope labeling establish that amyloid formation of hIAPP catalyzed by membranes includes a metastable intermediate with a similar structure at G24A25 in the FGAIL region as the corresponding intermediate in solution.
登录
查看更多内容
人类 IAPP 中淀粉样蛋白的形成机制：二聚体具有 β 链单体-单体界面。
影响因子：
15
作者：
Dupuis NF;Wu C;Shea JE;Bowers MT
通讯作者：
Bowers MT
DOI：
10.1021/acs.jpcb.1c05554
发表时间：
2021-08-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Dicke SS;Alperstein AM;Schueler KL;Stapleton DS;Simonett SP;Fields CR;Chalyavi F;Keller MP;Attie AD;Zanni MT
通讯作者：
Zanni MT
影响因子：
3.5
作者：
BETSHOLTZ, C;CHRISTMANSSON, L;WESTERMARK, P
通讯作者：
WESTERMARK, P
影响因子：
5
作者：
Rodriguez Camargo DC;Chia S;Menzies J;Mannini B;Meisl G;Lundqvist M;Pohl C;Bernfur K;Lattanzi V;Habchi J;Cohen SI;Knowles TPJ;Vendruscolo M;Linse S
通讯作者：
Linse S
影响因子：
4.3
作者：
Akter R;Cao P;Noor H;Ridgway Z;Tu LH;Wang H;Wong AG;Zhang X;Abedini A;Schmidt AM;Raleigh DP
通讯作者：
Raleigh DP