Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations.
Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations.
复制标题
DOI：
10.3390/molecules28104191
复制
发表时间：
2023-05-19
期刊：
影响因子：
--
通讯作者：
Cheng KH
中科院分区：
文献类型：
--
作者：
Nguyen N;Lewis A;Pham T;Sikazwe D;Cheng KH
人胰岛淀粉样多肽（hIAPP）在细胞膜上的聚集与淀粉样疾病有关。然而，这些hIAPP聚集体如何引发膜损伤的物理化学机制尚不清楚。利用粗粒化和全原子分子动力学模拟，我们研究了在存在或不存在阴离子脂质、磷脂酰丝氨酸（PS）和一种神经节苷脂（GM1）的情况下，脂质纳米域在相分离的筏膜上hIAPP聚集体的膜破坏和蛋白质折叠行为中的作用。我们的筏膜包含液态有序（Lo）、液态无序（Ld）、混合的Lo/Ld（Lod）、PS簇和GM1簇纳米尺寸的域。我们观察到，在不存在阴离子脂质的情况下，hIAPP聚集体结合到Lod域，但也结合到含有GM1簇和PS簇的域，在存在阴离子脂质的情况下亲和力更强。我们发现L16和I26是hIAPP结合到Lod和PS簇域的脂质锚定残基。最后，在膜结合的hIAPP聚集体周围的环形脂质壳中，脂质酰基链的有序性明显受到显著破坏，并且在较大的蛋白质聚集体中出现蛋白质折叠，特别是β -折叠的形成。我们提出，hIAPP与非阴离子和阴离子脂质纳米域的相互作用是与淀粉样疾病发病机制相关的膜损伤的关键分子事件。
The aggregation of human Islet Amyloid Polypeptide (hIAPP) on cell membranes is linked to amyloid diseases. However, the physio-chemical mechanisms of how these hIAPP aggregates trigger membrane damage are unclear. Using coarse-grained and all-atom molecular dynamics simulations, we investigated the role of lipid nanodomains in the presence or absence of anionic lipids, phosphatidylserine (PS), and a ganglioside (GM1), in the membrane disruption and protein folding behaviors of hIAPP aggregates on phase-separated raft membranes. Our raft membranes contain liquid-ordered (Lo), liquid-disordered (Ld), mixed Lo/Ld (Lod), PS-cluster, and GM1-cluster nanosized domains. We observed that hIAPP aggregates bound to the Lod domain in the absence of anionic lipids, but also to the GM1-cluster- and PS-cluster-containing domains, with stronger affinity in the presence of anionic lipids. We discovered that L16 and I26 are the lipid anchoring residues of hIAPP binding to the Lod and PS-cluster domains. Finally, significant lipid acyl chain order disruption in the annular lipid shells surrounding the membrane-bound hIAPP aggregates and protein folding, particularly beta-sheet formation, in larger protein aggregates were evident. We propose that the interactions of hIAPP and both non-anionic and anionic lipid nanodomains represent key molecular events of membrane damage associated with the pathogenesis of amyloid diseases.
登录
查看更多内容
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
用2D IR光谱检测到的膜催化HIAPP聚集期间的中间体。
影响因子：
4.1
作者：
Dicke, Sidney S.;Maj, Michal;Fields, Caitlyn R.;Zanni, Martin T.
通讯作者：
Zanni, Martin T.
影响因子：
5.5
作者：
de Jong, Djurre H.;Singh, Gurpreet;Marrink, Siewert J.
通讯作者：
Marrink, Siewert J.
影响因子：
3.9
作者：
Cornish J;Chamberlain SG;Owen D;Mott HR
通讯作者：
Mott HR
影响因子：
18.3
作者：
Brender, Jeffrey R.;Salamekh, Samer;Ramamoorthy, Ayyalusamy
通讯作者：
Ramamoorthy, Ayyalusamy