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首页> 外文期刊>The Journal of biological chemistry >Pathogenic Serum Amyloid A 1.1 Shows a Long Oligomer-rich Fibrillation Lag Phase Contrary to the Highly Amyloidogenic Non-pathogenic SAA2.2
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Pathogenic Serum Amyloid A 1.1 Shows a Long Oligomer-rich Fibrillation Lag Phase Contrary to the Highly Amyloidogenic Non-pathogenic SAA2.2

机译：致病性血清淀粉样蛋白A 1.1显示了与高淀粉样蛋白非致病性SAA2.2相反的长低聚物的富纤维化滞后阶段

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Serum amyloid A (SAA) is best known for being the main component of amyloid in the inflammation-related disease amyloid A (AA) amyloidosis. Despite the high sequence identity among different SAA isoforms, not all SAA proteins are pathogenic. In most mouse strains, the AA deposits mostly consist of SAA1.1. Conversely, the CE/J type mouse expresses a single non-pathogenic SAA2.2 protein that is 94% identical to SAA1.1. Here we show that SAA1.1 and SAA2.2 differ in their quaternary structure, fibrillation kinetics, prefibrillar oligomers, and fibril morphology. At 37 °C and inflammation-related SAA concentrations, SAA1.1 exhibits an oligomer-rich fibrillation lag phase of a few days, whereas SAA2.2 shows virtually no lag phase and forms small fibrils within a few hours. Deep UV resonance Raman, far UV-circular dichroism, atomic force microscopy, and fibrillation cross-seeding experiments suggest that SAA1.1 and SAA2.2 fibrils possess different morphology. Both the long-lived oligomers of pathogenic SAA1.1 and the fleeting prefibrillar oligomers of non-pathogenic SAA2.2, but not their respective amyloid fibrils, permeabilized synthetic bilayer membranes in vitro. This study represents the first comprehensive comparison between the biophysical properties of SAA isoforms with distinct pathogenicities, and the results suggest that structural and kinetic differences in the oligomerization-fibrillation of SAA1.1 and SAA2.2, more than their intrinsic amyloidogenicity, may contribute to their diverse pathogenicity.
机译：血清淀粉样蛋白A（SAA）是最符合炎症相关疾病淀粉样蛋白A（AA）淀粉样蛋白病的淀粉样蛋白的主要成分。尽管不同SAA同种型之间的序列同一性高，但并非所有SAA蛋白都是致病性的。在大多数小鼠菌株中，AA沉积物主要包括SAA1.1。相反，CE / J型小鼠表达了单一的非致病SAA2.2蛋白，其与SAA1.1相同。在这里，我们表明SAA1.1和SAA2.2在季结构，原纤运动动力学，前纤维状低聚物和原纤维形态方面不同。在37°C和炎症相关的SAA浓度下，SAA1.1表现出富含低聚物的原纤化滞后阶段，而SAA2.2几乎没有滞后阶段，在几小时内形成小型原纤维。深紫色共振拉曼，远紫外线二色性，原子力显微镜和原纤化交叉播种实验表明SAA1.1和SAA2.2原纤维具有不同的形态。致病SAA1.1的长寿命低聚物和非致病SAA2.2的短纤维寡聚体，但不是它们各自的淀粉样蛋白原纤维，透氧合成双层膜在体外。本研究代表了SAA同种型具有不同致病性的生物物理性质与结果表明SAA1.1和SAA2.2的寡聚纤维状的结构和动力学差异，可能有助于他们不同的致病性。

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