Exploring the relation between the oligomeric structure and membrane damage by a study on rat islet amyloid polypeptide.
Exploring the relation between the oligomeric structure and membrane damage by a study on rat islet amyloid polypeptide.
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通过大鼠胰岛淀粉样多肽的研究探讨寡聚结构与膜损伤的关系。
DOI：
10.1039/c7cp06468c
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Fei Li
中科院分区：
文献类型：
--
作者：
Tong Lu;Feihong Meng;Ying Wei;Yang Li;Chunyu Wang;Fei Li
前纤维中间体的形成不仅是淀粉样肽纤维化的关键阶段，也是其细胞毒性的关键阶段。大多数前原纤中间体的异质性和瞬时性使得它们难以分离、鉴定和表征。大鼠胰岛淀粉样多肽（rIAPP）在大多数溶液条件下具有微弱的原纤化倾向，并被发现具有细胞毒性，这使我们能够表征在各种低聚状态下形成的前原纤物种，并探索这些低聚物对膜损伤的机制。在本研究中，我们在各种条件下制备了rIAPP寡聚体，并利用CD，TEM，DLS，NMR光谱和泄漏试验表征了它们的结构，形态，大小，与POPC/POPG 4：1组成的膜的相互作用，以及对膜的破坏效率。我们发现，直径小于50 nm的rIAPP的寡聚化使rIAPP对膜的破坏性更大，而形成大于此限制的组装体则显著降低了rIAPP对膜的破坏性。具有较小尺寸和较高膜损伤效率的寡聚物种类具有与较强的膜结合相关的较长时间的α-螺旋在膜上的稳定性。我们的研究结果表明，寡聚体的大小和疏水暴露之间的相互作用是牵连的膜损伤的机制。疏水性暴露与破坏性效力之间的正相关性仅对尺寸小于一定尺寸限度的寡聚体有效。
The formation of prefibrillar intermediates is a key stage not only for the fibrillation of amyloid peptides but also for their cytotoxicity. The heterogeneous and transient nature of most prefibrillar intermediates make them difficult to be separated, identified, and characterized. Rat islet amyloid polypeptide (rIAPP) has a weak propensity of fibrillation under most solution conditions and is found to be cytotoxic, which enables us to characterize prefibrillar species formed at various oligomeric states and explore the mechanism of membrane damage by these oligomers. In the present study, we prepared rIAPP oligomers under various conditions and characterized their structures, morphologies, sizes, interactions with the membrane composed of POPC/POPG 4 : 1, and disruptive efficiencies to the membrane using CD, TEM, DLS, NMR spectroscopy, and leaking assays. We found that oligomerization of rIAPP below a size limit of ∼50 nm in diameter rendered rIAPP more damaging to the membrane, whereas the formation of assemblies with sizes above this limit dramatically decreased the disruptive potency of rIAPP to the membrane. The oligomer species with smaller sizes and higher membrane-damage efficiencies have a longer time stability of α-helix at the membrane that is associated with a stronger membrane binding. Our findings show that interplay between the oligomeric size and hydrophobic exposure is implicated in the mechanism of membrane damage. The positive correlation between hydrophobic exposure and disruptive potency is valid only for the oligomers with sizes smaller than certain size limit.
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