Amyloid fibril formation and chaperone-like activity of peptides from αA-Crystallin
Amyloid fibril formation and chaperone-like activity of peptides from αA-Crystallin
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DOI：
10.1021/bi701823g
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发表时间：
2008-03-04
期刊：
影响因子：
2.9
通讯作者：
Hamada, Daizo
中科院分区：
文献类型：
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作者：
Tanaka, Naoki;Tanaka, Ryoji;Hamada, Daizo
α A-晶状体蛋白 (α AC) 是眼晶状体的主要成分，具有类似伴侣的活性，负责维持眼晶状体的透明度。据报道，与 α AC 假定的底物结合位点相对应的合成肽可以防止蛋白质聚集 [Sharma, K. K., et al. (2000) J.Biol。化学。 275、3767-3771]。在这项研究中，我们发现这些肽，α AC(70-88)、对应于 α AC 70-88 氨基酸的肽 (KFVIFLDVKHFSPEDLTVK) 和 α AC(71-88)，抑制了淀粉样β蛋白 (Aβ) 的淀粉样原纤维形成。另一方面，虽然α AC(71-88)对胰岛素表现出分子伴侣样活性，但α AC(70-88)和α AC(70-88)K70D促进由胰岛素和这些肽在其溶液混合物中组成的聚集体的快速生长。有趣的是，我们发现α AC(71-88)本身也可以形成淀粉样原纤维。 α AC 肽的分子伴侣样活性可能与其淀粉样原纤维形成的倾向有关。对 α AC 肽变体的分析表明，F71 对于淀粉样蛋白的形成很重要，有趣的是，之前已发现该残基对于分子伴侣样活性至关重要。还用较短的肽 α AC(70-76)K70D 观察到淀粉样原纤维的形成，表明即使 C 端序列显着缺失，形成淀粉样原纤维的能力仍然保持。 α AC(70-88) 中淀粉样原纤维的形成受到抑制，表明底物结合位点中的 K70 可能在抑制 α AC 淀粉样原纤维形成中发挥作用，这与最近关于在易于聚集的疏水序列侧翼区域中存在聚集抑制因子的提议一致。
alpha A-Crystallin (alpha AC), a major component of eye lens, exhibits chaperone-like activity and is responsible for maintaining eye lens transparency. Synthetic peptides which corresponded to the putative substrate-binding site of alpha AC have been reported to prevent aggregation of proteins [Sharma, K. K., et al. (2000) J. Biol. Chem. 275, 3767-3771]. In this study, we found that these peptides, alpha AC(70-88), the peptide corresponding to amino acids 70-88 of alpha AC (KFVIFLDVKHFSPEDLTVK), and alpha AC(71-88), suppressed the amyloid fibril formation of amyloid beta protein (A beta). On the other hand, while alpha AC(71-88) exhibited chaperone-like activity toward insulin, alpha AC(70-88) and alpha AC(70-88)K70D promoted rapid growth of aggregates consisting of insulin and these peptides in their solution mixtures. Interestingly, we found that alpha AC(71-88) itself can also form amyloid fibrils. It is possible that the chaperone-like activity of the alpha AC peptides is potentially related to their propensity for amyloid fibril formation. Analysis of variants of the alpha AC peptides suggested that F71 is important for amyloid formation, and interestingly, this same residue has previously been found to be essential for chaperone-like activity. Amyloid fibril formation was also observed with the shorter peptide, alpha AC(70-76)K70D, showing that the ability to form amyloid fibrils is maintained even with significant deletion of the C-terminal sequence. The formation of amyloid fibril was suppressed in alpha AC(70-88), suggesting that the K70 in the substrate binding site may play a role in suppressing the amyloid fibril formation of alpha AC, which agreed with recent proposals about the presence of an aggregation suppressor in the region flanking aggregation-prone hydrophobic sequences.