Sticker-and-spacer model for amyloid beta condensation and fibrillation.
Sticker-and-spacer model for amyloid beta condensation and fibrillation.
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DOI：
10.3389/fnmol.2022.962526
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发表时间：
2022
影响因子：
4.8
通讯作者：
Schaefer, Charley
中科院分区：
文献类型：
--
作者：
Connor, Jack P. P.;Quinn, Steven D. D.;Schaefer, Charley
关键词：
阿尔茨海默病的一个主要致病标志是患者大脑中存在由β淀粉样蛋白（Aβ）肽组成的神经毒性斑块。斑块形成的途径仍然难以捉摸，尽管Aβ1 - 40约占Aβ库的90%，但在这些斑块中Aβ1 - 42的存在似乎是一些线索。我们假设这种不对称是由Aβ1−42中掺入的两个额外氨基酸的疏水性驱动的。为了在单分子水平上研究这一假设，我们开发了一种未折叠a β的分子“黏贴-间隔晶格模型”。模型蛋白有一个可以可逆地二聚并拉长成半柔性线性链的标签。由亲水间隔剂编码的排斥体积相互作用阻碍了生长，但疏水间隔剂的吸引相互作用使其具有合作性。对于足够强的疏水性，链经过液-液相分离（LLPS）形成有利于纤维成核的凝聚物。我们发现，在a β1−40和a β1−42的混合物中，少量的a β1−40使LLPS的临界浓度降低。本研究为LLPS凝聚体作为聚集前体的假设提供了理论支持，并从疏水相互作用的角度解释了聚集体富集a β1−42的原因。
A major pathogenic hallmark of Alzheimer's disease is the presence of neurotoxic plaques composed of amyloid beta (Aβ) peptides in patients' brains. The pathway of plaque formation remains elusive, though some clues appear to lie in the dominant presence of Aβ1 − 42 in these plaques despite Aβ1−40 making up approximately 90% of the Aβ pool. We hypothesize that this asymmetry is driven by the hydrophobicity of the two extra amino acids that are incorporated in Aβ1−42. To investigate this hypothesis at the level of single molecules, we have developed a molecular “sticker-and-spacer lattice model” of unfolded Aβ. The model protein has a single sticker that may reversibly dimerise and elongate into semi-flexible linear chains. The growth is hampered by excluded-volume interactions that are encoded by the hydrophilic spacers but are rendered cooperative by the attractive interactions of hydrophobic spacers. For sufficiently strong hydrophobicity, the chains undergo liquid-liquid phase-separation (LLPS) into condensates that facilitate the nucleation of fibers. We find that a small fraction of Aβ1−40 in a mixture of Aβ1−40 and Aβ1−42 shifts the critical concentration for LLPS to lower values. This study provides theoretical support for the hypothesis that LLPS condensates act as a precursor for aggregation and provides an explanation for the Aβ1−42-enrichment of aggregates in terms of hydrophobic interactions.
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DOI：
10.1016/j.bbadis.2008.06.003
发表时间：
2008-09-01
影响因子：
6.2
作者：
Chafekar, Sidhartha M.;Baas, Frank;Scheper, Wiep
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DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
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影响因子：
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作者：
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