Serag Ahmed A, Altenbach Christian, Gingery Mari, Hubbell Wayne L, Yeates Todd O
Molecular Biology Institute and School of Medicine, University of California, Los Angeles, California 90095, USA.
Nat Struct Biol. 2002 Oct;9(10):734-9. doi: 10.1038/nsb838.
Amyloid fibrils are associated with several disease states, but their structures have yet to be fully defined. Here we use site-directed spin labeling to explain some of the specific interactions that are formed between subunits when the protein transthyretin (TTR) assembles into amyloid fibrils, which are associated with both spontaneous and familial amyloid diseases in humans. The results suggest that fibrils are formed when a major conformational change displaces the terminal beta-strand from the edge of a beta-sheet in the native structure, exposing the penultimate strand. The newly exposed strand then allows a novel beta-sheet interaction to form between the TTR subunits. This interaction and another previously identified subunit association lead to a plausible model for the specific sequence of beta-strands in one of the indefinitely repeating beta-sheets of TTR amyloid, which is formed by a head-to-head, tail-to-tail arrangement of subunits.
淀粉样纤维与多种疾病状态相关，但其结构尚未完全明确。在此，我们运用定点自旋标记法来解释蛋白质转甲状腺素蛋白（TTR）组装成淀粉样纤维时亚基之间形成的一些特定相互作用，TTR淀粉样纤维与人类的自发性和家族性淀粉样疾病均有关联。结果表明，当一个主要的构象变化将末端β链从天然结构中β折叠的边缘移开，暴露出倒数第二条链时，纤维就会形成。新暴露的链随后允许在TTR亚基之间形成一种新的β折叠相互作用。这种相互作用以及另一种先前确定的亚基关联导致了一个关于TTR淀粉样纤维无限重复β折叠之一中β链特定序列的合理模型，该β折叠是由亚基的头对头、尾对尾排列形成的。
