Growth of β2-microglobulin-related amyloid fibrils by non-esterified fatty acids at a neutral pH
Growth of β2-microglobulin-related amyloid fibrils by non-esterified fatty acids at a neutral pH
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DOI：
10.1042/bj20080543
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发表时间：
2008-12-01
影响因子：
4.1
通讯作者：
Naiki, Hironobu
中科院分区：
文献类型：
--
作者：
Hasegawa, Kazuhiro;Tsutsumi-Yasuhara, Shinobu;Naiki, Hironobu
β2M（β(2)-微球蛋白相关）淀粉样变性是长期透析患者常见且严重的并发症。 β2-m（β(2)-微球蛋白）的部分解折叠可能对其在体内组装成 Aβ2M 淀粉样原纤维至关重要。尽管临界胶束浓度附近的SDS在体外诱导β2-m部分解折叠为所有含有α-螺旋的易于聚集的淀粉样蛋白形成构象异构体以及随后的淀粉样原纤维形成，但在接近生理条件下具有相似活性的生物分子仍然未知。使用硫黄素 T 荧光光谱、CD 光谱和电子显微镜检查了各种 NEFA（非酯化脂肪酸）（循环中代表性阴离子两亲化合物）对中性 pH 条件下 A beta 2M 淀粉样原纤维生长的影响。生理相关浓度的月桂酸盐、肉豆蔻酸盐、油酸盐、亚油酸盐以及棕榈酸盐、硬脂酸盐、油酸盐和亚油酸盐的混合物，通过部分展开β2-m的致密结构来诱导原纤维在中性pH下的生长，以形成所有易于聚集的淀粉样蛋白形成构象。在人血清白蛋白存在的情况下，当这些NEFA的浓度超过白蛋白的结合能力时，这些NEFA也会诱导原纤维的生长，这表明未结合的NEFA而不是白蛋白结合的NEFA在体外诱导原纤维生长反应。这些结果表明 NEFA 参与 A β 2M 淀粉样变性的发展以及 A β 2M 淀粉样变性的发病机制。
A beta 2M (beta(2)-microglobulin-related) amyloidosis is a frequent and serious complication in patients on long-term dialysis. Partial unfolding of beta 2-m (beta(2)-microglobulin) may be essential to its assembly into A beta 2M amyloid fibrils in vivo. Although SDS around the critical micelle concentration induces partial unfolding of beta 2-m to ail a-helix-containing aggregation-prone amyloidogenic conformer and subsequent amyloid fibril formation in vitro, the biological molecules with similar activity under near-physiological conditions are Still unknown. The effect of various NEFAs (non-esterified fatty acids), which are representative anionic amphipathic compounds in the circulation, on the growth of A beta 2M amyloid fibrils at a neutral pH was examined using fluorescence spectroscopy with thioflavin T, CD spectroscopy, and electron microscopy. Physiologically relevant concentrations of laurate, myristate, oleate, linoleate, and mixtures of palmitate, stearate, oleate and linoleate, induced the growth of fibrils at a neutral pH by partially unfolding the compact structure of beta 2-m to ail aggregation-prone amyloidogenic conformer. In the presence of human serum albumin, these NEFAs also induced the growth of fibrils when their concentrations exceeded the binding capacity of albumin, indicating that the unbound NEFAs rather than albumin-bound NEFAs induce the fibril growth reaction in vitro. These results suggest the involvement of NEFAs in the development of A beta 2M amyloidosis, and in the pathogenesis of A beta 2M amyloidosis.