Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin: roles of shear flow, hydrophobic surfaces, and α-crystallin.
Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin: roles of shear flow, hydrophobic surfaces, and α-crystallin.
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DOI：
10.1074/jbc.m113.498857
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发表时间：
2013-10-25
期刊：
影响因子：
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通讯作者：
Bellotti V
中科院分区：
文献类型：
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作者：
Mangione PP;Esposito G;Relini A;Raimondi S;Porcari R;Giorgetti S;Corazza A;Fogolari F;Penco A;Goto Y;Lee YH;Yagi H;Cecconi C;Naqvi MM;Gillmore JD;Hawkins PN;Chiti F;Rolandi R;Taylor GW;Pepys MB;Stoppini M;Bellotti V
背景：我们最近发现了第一个天然的人类β2-微球蛋白变体D 76 N，作为一种淀粉样蛋白。结果：疏水表面上的流体流动触发其淀粉样纤维形成。α-晶状体蛋白伴侣蛋白抑制野生型β2-微球蛋白的变体介导的共聚集。结论：这些机制可能反映了体内淀粉样蛋白的球状蛋白一般。意义：我们的结果阐明了淀粉样蛋白沉积的分子病理生理学。系统性淀粉样变性是由天然球状蛋白的错误折叠引起的致命疾病，其然后在细胞外聚集为不溶性纤维，损害受影响器官的结构和功能。体内淀粉样纤维的形成知之甚少。我们最近在一个迟发性致死性遗传性系统性淀粉样变性的新表型家族中鉴定了人β2-微球蛋白（β 2 m）的第一个天然结构变体D 76 N，即普遍存在的I类主要组织相容性抗原轻链，作为淀粉样纤维蛋白。在这里，我们发现，独特的，D 76 N β 2 m容易形成淀粉样纤维在体外生理细胞外条件下。球状原生褶皱过渡到纤维状状态是通过暴露于生理强度剪切流下的疏水-亲水界面引发的。野生型β 2 m在体外被变体募集到淀粉样蛋白原纤维中，但在体内沉积的淀粉样蛋白中不存在。这可能是因为，正如我们在这里显示，这种招聘是由伴侣活性抑制。我们的研究结果表明，一般的机械原理，在体内淀粉样纤维的球状蛋白，以前模糊的过程。阐明临床淀粉样变性中这一关键的致病事件也有助于解释迄今为止淀粉样蛋白沉积的神秘时间和位置。
Background: We recently discovered the first natural human β2-microglobulin variant, D76N, as an amyloidogenic protein. Results: Fluid flow on hydrophobic surfaces triggers its amyloid fibrillogenesis. The α-crystallin chaperone inhibits variant-mediated co-aggregation of wild type β2-microglobulin. Conclusion: These mechanisms likely reflect in vivo amyloidogenesis by globular proteins in general. Significance: Our results elucidate the molecular pathophysiology of amyloid deposition. Systemic amyloidosis is a fatal disease caused by misfolding of native globular proteins, which then aggregate extracellularly as insoluble fibrils, damaging the structure and function of affected organs. The formation of amyloid fibrils in vivo is poorly understood. We recently identified the first naturally occurring structural variant, D76N, of human β2-microglobulin (β2m), the ubiquitous light chain of class I major histocompatibility antigens, as the amyloid fibril protein in a family with a new phenotype of late onset fatal hereditary systemic amyloidosis. Here we show that, uniquely, D76N β2m readily forms amyloid fibrils in vitro under physiological extracellular conditions. The globular native fold transition to the fibrillar state is primed by exposure to a hydrophobic-hydrophilic interface under physiological intensity shear flow. Wild type β2m is recruited by the variant into amyloid fibrils in vitro but is absent from amyloid deposited in vivo. This may be because, as we show here, such recruitment is inhibited by chaperone activity. Our results suggest general mechanistic principles of in vivo amyloid fibrillogenesis by globular proteins, a previously obscure process. Elucidation of this crucial causative event in clinical amyloidosis should also help to explain the hitherto mysterious timing and location of amyloid deposition.