Influence of the carboxy terminus of serum amyloid A on protein oligomerization, misfolding, and fibril formation.
Influence of the carboxy terminus of serum amyloid A on protein oligomerization, misfolding, and fibril formation.
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DOI：
10.1021/bi201903s
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发表时间：
2012-04-10
期刊：
影响因子：
2.9
通讯作者：
Kane, Ravi S.
中科院分区：
文献类型：
--
作者：
Patke, Sanket;Maheshwari, Ronak;Litt, Jeffrey;Srinivasan, Saipraveen;Aguilera, J. Javier;Colon, Wilfredo;Kane, Ravi S.
血清淀粉样蛋白A(SAA)的纤维沉积与淀粉样蛋白A(AA)病有关。我们使用CE/J小鼠品系的SAA亚型SAA2.2作为模型系统来探索SAA的内在结构和生物物理性质。尽管SAA2.2在体内是非致病的，但它在体外会自发形成纤维，这表明SAA蛋白本身就是淀粉样变性的。然而，虽然SAA的氨基末端对纤维形成的重要性已经被很好地记录下来，但富含脯氨酸和推测无序的羧基末端的影响仍然知之甚少。为了阐明羧基在SAA齐聚和纤化中的内在作用，我们截短了SAA2.2的富含脯氨酸的最后13个残基。我们发现，与全长SAA2.2不同，羧基末端截短的SAA2.2(SAA2.2ΔC)不会齐聚成六聚体或八聚体，而是形成高相对分子质量的可溶性聚集体。此外，SAA2.2ΔC还显示出纤维形成速度的显著降低。有趣的是，当等摩尔变性的SAA2.2和SAA2.2ΔC混合并允许一起重折叠时，混合物形成八聚体并表现出快速的原纤化动力学，类似于全长SAA2.2。这些结果表明，SAA的羧基末端在所有脊椎动物的SAA序列中高度保守，可能发挥着重要的结构作用，包括调节SAA的折叠、寡聚、错误折叠和纤颤。
The fibrillar deposition of serum amyloid A (SAA) has been linked to the disease amyloid A (AA) amyloidosis. We have used the SAA isoform, SAA2.2, from the CE/J mouse strain, as a model system to explore the inherent structural and biophysical properties of SAA. Despite its non-pathogenic nature in vivo, SAA2.2 spontaneously forms fibrils in vitro, suggesting that SAA proteins are inherently amyloidogenic. However, while the importance of the amino-terminus of SAA for fibril formation has been well documented, the influence of the proline-rich and presumably disordered carboxy-terminus remains poorly understood. To clarify the inherent role of the carboxy-terminus in the oligomerization and fibrillation of SAA, we truncated the proline-rich final 13 residues of SAA2.2. We found that unlike full-length SAA2.2, the carboxy-terminal truncated SAA2.2 (SAA2.2ΔC) did not oligomerize to a hexamer or octamer, but formed a high molecular weight soluble aggregate. Moreover, SAA2.2ΔC also exhibited a pronounced decrease in the rate of fibril formation. Intriguingly, when equimolar amounts of denatured SAA2.2 and SAA2.2ΔC were mixed and allowed to refold together, the mixture formed an octamer and exhibited rapid fibrillation kinetics, similar to those for full-length SAA2.2. These results suggest that the carboxy-terminus of SAA, which is highly conserved among SAA sequences in all vertebrates, might play important structural roles, including modulating the folding, oligomerization, misfolding, and fibrillation of SAA.
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影响因子：
3.7
作者：
MARHAUG, G
通讯作者：
MARHAUG, G
DOI：
10.1111/j.1749-6632.1982.tb22124.x
发表时间：
1982-01-01
影响因子：
5.2
作者：
KUSHNER, I
通讯作者：
KUSHNER, I
影响因子：
3.5
作者：
ERICSSON, LH;ERIKSEN, N;BENDITT, EP
通讯作者：
BENDITT, EP
影响因子：
4.8
作者：
Elimova, Elena;Kisilevsky, Robert;Ancsin, John B.
通讯作者：
Ancsin, John B.
DOI：
10.1073/pnas.0502287102
发表时间：
2005-05-03
影响因子：
11.1
作者：
Li, JP;Galvis, MLE;Lindahl, U
通讯作者：
Lindahl, U