Distinct Modes of Action of IAPP Oligomers on Membranes.
Distinct Modes of Action of IAPP Oligomers on Membranes.
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IAPP 低聚物对膜的独特作用模式。
DOI：
10.1021/acs.jcim.1c00767
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发表时间：
2021
影响因子：
5.6
通讯作者：
Lazaridis,Themis
中科院分区：
文献类型：
--
作者：
Sepehri,Aliasghar;Nepal,Binod;Lazaridis,Themis
胰岛淀粉样多肽（IAPP，也称为胰淀素）是由胰腺β细胞与胰岛素共同分泌的肽激素，并在II型糖尿病中形成淀粉样蛋白聚集体。各种证据表明，这种肽的寡聚体可能通过破坏或形成细胞膜中的孔而诱导毒性，但这些孔的结构是未知的。在这里，我们使用隐式膜建模创建螺旋和β结构肽的孔模型，并使用多微秒全原子模拟测试其稳定性。我们发现，螺旋肽的行为类似于抗菌肽，它们保持稳定插入在一个高度倾斜或部分展开的配置，创造一个狭窄的水通道。平行螺旋方向产生了稍大的孔隙。平行β-发夹的八聚体β桶在膜中是高度稳定的，而由反平行发夹构成的相应桶则不是。我们建议某些实验探测螺旋孔状态，而其他实验探测β结构孔状态;这为体内毒性和体外脂质体透化实验之间有时观察到的缺乏相关性提供了可能的解释。
Islet amyloid polypeptide (IAPP, also known as amylin) is a peptide hormone that is co-secreted with insulin by pancreatic β-cells and forms amyloid aggregates in type II diabetes. Various lines of evidence indicate that oligomers of this peptide may induce toxicity by disrupting or forming pores in cell membranes, but the structure of these pores is unknown. Here, we create models of pores for both helical and β-structured peptides using implicit membrane modeling and test their stability using multimicrosecond all-atom simulations. We find that the helical peptides behave similarly to antimicrobial peptides; they remain stably inserted in a highly tilted or partially unfolded configuration creating a narrow water channel. Parallel helix orientation creates a somewhat larger pore. An octameric β barrel of parallel β-hairpins is highly stable in the membrane, whereas the corresponding barrel made of antiparallel hairpins is not. We propose that certain experiments probe the helical pore state while others probe the β-structured pore state; this provides a possible explanation for lack of correlation that is sometimes observed between in vivo toxicity and in vitro liposome permeabilization experiments.