Nanobiophysics, MESA+ Institute for Nanotechnology, University of Twente, PO Box 217, 7500AE Enschede, The Netherlands.
Mol Neurobiol. 2013 Apr;47(2):613-21. doi: 10.1007/s12035-012-8331-4. Epub 2012 Sep 6.
In many human diseases, oligomeric species of amyloid proteins may play a pivotal role in cytotoxicity. Many lines of evidence indicate that permeabilization of cellular membranes by amyloid oligomers may be the key factor in disrupting cellular homeostasis. However, the exact mechanisms by which the membrane integrity is impaired remain elusive. One prevailing hypothesis, the so-called amyloid pore hypothesis, assumes that annular oligomeric species embed into lipid bilayers forming transbilayer protein channels. Alternatively, an increased membrane permeability could be caused by thinning of the hydrophobic core of the lipid bilayer due to the incorporation of the oligomers between the tightly packed lipids, which would facilitate the transport of small molecules across the membrane. In this review, we briefly recapitulate our findings on the structure of α-synuclein oligomers and the factors influencing their interaction with lipid bilayers. Our results, combined with work from other groups, suggest that α-synuclein oligomers do not necessarily form pore-like structures. The emerging consensus is that local structural rearrangements of the protein lead to insertion of specific regions into the hydrophobic core of the lipid bilayer, thereby disrupting the lipid packing.
在许多人类疾病中，淀粉样蛋白的寡聚体可能在细胞毒性中发挥关键作用。许多证据表明，淀粉样寡聚体对细胞膜的通透性可能是破坏细胞内稳态的关键因素。然而，确切的膜完整性受损机制仍不清楚。一种流行的假说，即所谓的淀粉样孔假说，假设环形寡聚体嵌入脂质双层形成跨膜蛋白通道。或者，由于寡聚体在紧密堆积的脂质之间的掺入，导致脂质双层的疏水区变薄，从而增加了膜的通透性，这将促进小分子穿过膜的运输。在这篇综述中，我们简要回顾了我们关于α-突触核蛋白寡聚体结构以及影响其与脂质双层相互作用的因素的发现。我们的结果与其他小组的工作相结合，表明α-突触核蛋白寡聚体不一定形成孔状结构。新兴的共识是，蛋白质的局部结构重排导致特定区域插入脂质双层的疏水区，从而破坏脂质堆积。
