Human amylin oligomer growth and fibril elongation define two distinct phases in amyloid formation
Human amylin oligomer growth and fibril elongation define two distinct phases in amyloid formation
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DOI：
10.1074/jbc.m312452200
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发表时间：
2004-03-26
影响因子：
4.8
通讯作者：
Aebi, U
中科院分区：
文献类型：
--
作者：
Green, JD;Goldsbury, C;Aebi, U
人胰岛淀粉样多肽 (hA) 是一种 37 个氨基酸的多肽，是能够形成淀粉样纤维并引起疾病的多种肽之一。它是与 2 型糖尿病相关的胰腺淀粉样蛋白沉积物的主要成分。人们对早期组装中间体而不是成熟原纤维作为细胞毒性剂的兴趣日益浓厚，导致这项研究通过原子力显微镜捕获了最小的 hA 寡聚物。它们的高度为 2.3 +/- 1.9 nm，长度为 23 +/- 14 nm，估计由 16 个 hA 分子组成。低聚物首先生长到约 6 nm 的高度，然后开始显着伸长成原纤维。刚果红抑制 hA 寡聚物的伸长，但不抑制高度的生长。因此，在 hA 原纤维形成中鉴定出两个不同的阶段：寡聚物横向生长，随后纵向生长成成熟原纤维。这些观察结果表明，成熟的原纤维是通过全宽寡聚物的纵向生长直接组装的，使得通过原原纤维的横向缔合进行组装的可能性似乎较小。
Human amylin (hA), a 37-amino-acid polypeptide, is one of a number of peptides with the ability to form amyloid fibrils and cause disease. It is the main constituent of the pancreatic amyloid deposits associated with type 2 diabetes. Increasing interest in early assembly intermediates rather than the mature fibrils as the cytotoxic agent has led to this study in which the smallest hA oligomers have been captured by atomic force microscopy. These are 2.3 +/- 1.9 nm in height, 23 +/- 14 nm in length, and consist of an estimated 16 hA molecules. Oligomers first grow to a height of about 6 nm before they begin to significantly elongate into fibrils. Congo red inhibits elongation but not the growth in height of hA oligomers. Two distinct phases have thus been identified in hA fibrillogenesis: lateral growth of oligomers followed by longitudinal growth into mature fibrils. These observations suggest that mature fibrils are assembled directly via longitudinal growth of full-width oligomers, making assembly by lateral association of protofibrils appear less likely.