Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis
Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis
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DOI：
10.1073/pnas.1707120114
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发表时间：
2017-08-08
影响因子：
11.1
通讯作者：
Gursky, Olga
中科院分区：
文献类型：
--
作者：
Jayaraman, Shobini;Gantz, Donald L.;Gursky, Olga
血清淀粉样蛋白A（SAA）是一种急性时相血浆蛋白，在先天免疫和脂质稳态中起作用。SAA是反应性AA淀粉样变性的蛋白质前体，其是慢性炎症的主要并发症，并且是全世界最常见的人类系统性淀粉样疾病之一。大多数循环SAA通过与血浆高密度脂蛋白结合而免受蛋白水解和错误折叠。然而，未结合的可溶性SAA本质上是无序的，并且在溶酶体引发的过程中快速降解或形成淀粉样蛋白。虽然酸性pH促进淀粉样纤维的形成，这种蛋白质和许多其他蛋白质，分子基础尚不清楚。我们使用了一系列光谱、生物化学和结构方法来揭示，在pH 3.5-4.5时，鼠SAA 1形成稳定的可溶性寡聚体，其在pH 4.3时最大程度地折叠，具有类似于35%的α-螺旋，并且对蛋白水解具有异常的抗性。在溶液中，这些低聚物既不容易转化成成熟的原纤维，也不以载脂蛋白的典型方式通过其两亲性α-螺旋结合脂质表面。相反，这些低聚物经历了脂囊泡催化的a-螺旋到β-折叠的转化，并破坏了这些囊泡，表明具有膜溶解潜力。我们的研究结果为AA淀粉样变性的溶酶体起源提供了一个解释。他们认为SAA寡聚体在pH 3.5-4.5下的高结构稳定性和对蛋白水解的抗性帮助它们逃避溶酶体降解，促进SAA在溶酶体中的积累，并最终破坏细胞膜并释放细胞内淀粉样蛋白。我们认为这些可溶性前纤维低聚物为我们理解AA淀粉样变性的发展提供了一个缺失的环节。
Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5-4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with similar to 35% a-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic a-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an a-helix to beta-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5-4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.