Elucidation of the Aggregation Pathways of Helix-Turn-Helix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation.
Elucidation of the Aggregation Pathways of Helix-Turn-Helix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation.
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DOI：
10.1021/acs.biochem.5b00414
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发表时间：
2015-07-07
期刊：
影响因子：
2.9
通讯作者：
Bowers MT
中科院分区：
文献类型：
--
作者：
Do TD;Chamas A;Zheng X;Barnes A;Chang D;Veldstra T;Takhar H;Dressler N;Trapp B;Miller K;McMahon A;Meredith SC;Shea JE;Lazar Cantrell K;Bowers MT
蛋白质聚集成纤维状聚集体通常涉及天然单体转化成富含β-片层的寡聚体。这种普遍的观察低估了α-螺旋片段在聚集级联中的重要性。在这里，使用实验技术和加速分子动力学模拟相结合，我们调查的43个残基，载脂蛋白A-I模拟肽及其E21 Q和D26 N突变体的聚集。我们的研究表明，螺旋片段不采用交叉β原纤维的强烈倾向。肽的螺旋-转角-螺旋单体构象保留在成熟的原纤维中。此外，我们揭示了相反的效果突变和附近的转区域在这些肽的自组装。我们发现E21-R24盐桥是螺旋-转角-螺旋折叠的主要贡献者，随后导致丰富的原纤维形成。另一方面，折叠天然螺旋-转角-螺旋不需要K19-D26相互作用。然而，带电荷的D26残基的去除降低了螺旋-转角-螺旋单体的稳定性，并因此减少了聚集。最后，我们基于螺旋-转角-螺旋二聚体的平行堆叠，为载脂蛋白A-I的螺旋-转角-螺旋肽提供了更精确的组装模型。
Aggregation of proteins to fiber-like aggregates often involves a transformation of native monomers to β-sheet-rich oligomers. This general observation underestimates the importance of α-helical segments in the aggregation cascade. Here, using a combination of experimental techniques and accelerated molecular dynamics simulations, we investigate the aggregation of a 43-residue, apolipoprotein A-I mimetic peptide and its E21Q and D26N mutants. Our study indicates a strong propensity of helical segments not to adopt cross-β fibrils. The helix-turn-helix monomeric conformation of the peptides is preserved in the mature fibrils. Furthermore, we reveal opposite effects of mutations on and near the turn region in the self-assembly of these peptides. We show that the E21-R24 salt bridge is a major contributor to helix-turn-helix folding, subsequently leading to abundant fibril formation. On the other hand, the K19-D26 interaction is not required to fold the native helix-turn-helix. However, removal of the charged D26 residue decreases the stability of helix-turn-helix monomer, and consequently reduces aggregation. Finally, we provide a more refined assembly model for the helix-turn-helix peptides from apolipoprotein A-I based on the parallel stacking of helix-turn-helix dimers.