Green Janelle D, Goldsbury Claire, Kistler Joerg, Cooper Garth J S, Aebi Ueli
M. E. Müller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
J Biol Chem. 2004 Mar 26;279(13):12206-12. doi: 10.1074/jbc.M312452200. Epub 2004 Jan 1.
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.
人胰岛淀粉样多肽（hA）是一种由37个氨基酸组成的多肽，是众多能够形成淀粉样原纤维并引发疾病的肽类之一。它是与2型糖尿病相关的胰腺淀粉样沉积物的主要成分。由于越来越多的人关注早期组装中间体而非成熟原纤维作为细胞毒性剂，因此开展了本研究，通过原子力显微镜捕获了最小的hA寡聚体。这些寡聚体高度为2.3±1.9纳米，长度为23±14纳米，估计由16个hA分子组成。寡聚体在开始显著伸长形成原纤维之前，首先生长到约6纳米的高度。刚果红抑制hA寡聚体的伸长，但不抑制其高度增长。因此，在hA纤维形成过程中确定了两个不同阶段：寡聚体的横向生长，随后纵向生长形成成熟原纤维。这些观察结果表明，成熟原纤维是通过全宽寡聚体的纵向生长直接组装而成的，这使得原纤维通过横向缔合进行组装的可能性较小。
