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首页> 外文期刊>Biochemistry >Molecular Level Insights into Thermally Induced alpha-Chymotrypsinogen A Amyloid Aggregation Mechanism and Semiflexible Protofibril Morphology
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Molecular Level Insights into Thermally Induced alpha-Chymotrypsinogen A Amyloid Aggregation Mechanism and Semiflexible Protofibril Morphology

机译：分子水平的洞察力热诱导α-胰凝乳蛋白酶原A淀粉样蛋白聚集机制和半柔性原纤维形态。

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Understanding nonnative protein aggregation is critical not only to a number of amyloidosis disorders but also for the development of effective and safe biopharmaceuticals. In a series of previous studies [Weiss et al. (2007) Biophys. J. 93, 4392-4403; Andrews et al. (2007) Biochemistry 46, 7558-7571; Andrews et al. (2008) Biochemistry 47, 2397-2403], alpha-chymotrypsinogen A (aCgn) and bovine granulocyte colony stimulating factor (bG-CSF) have been shown to exhibit the kinetic and morphological features of other nonnative aggregating proteins at low pH and ionic strength. In this study, we investigated the structural mechanism of aCgn aggregation. The resultant aCgn aggregates were found to be soluble and exhibited semiflexible filamentous aggregate morphology under transmission electron microscopy. In addition, the filamentous aggregates were demonstrated to possess amyloid characteristics by both Congo red binding and X-ray diffraction. Peptide level hydrogen exchange (HX) analysis suggested that a buried native beta-sheet comprised of three peptide segments (39-46, 51-64, and 106-114) reorganizes into the cross-beta amyloid core of aCgn aggregates and that at least similar to 50% of the sequence adopts a disordered structure in the aggregates. Furthermore, the equimolar, bimodal HX labeling distribution observed for three reported peptides (65-102, 160-180, and 229-245) suggested a heterogeneous assembly of two molecular conformations in aCgn aggregates. This demonstrates that extended beta-sheet interactions typical of the amyloid are sufficiently strong that a relatively small fraction of polypeptide sequence can drive formation of filamentous aggregates even under conditions favoring colloidal stability.
机译：理解非天然蛋白质聚集不仅对于许多淀粉样变性病至关重要，而且对于开发有效和安全的生物药物也至关重要。在一系列先前的研究中[Weiss et al。 （2007）生物物理。 J.93，4392-4403;安德鲁斯等。 （2007）Biochemistry 46，7558-7571;安德鲁斯等。 （2008）Biochemistry 47，2397-2403]，α-胰凝乳蛋白酶原A（aCgn）和牛粒细胞集落刺激因子（bG-CSF）已显示在低pH和离子强度下具有其他非天然聚集蛋白的动力学和形态特征。 。在这项研究中，我们研究了aCgn聚集的结构机制。在透射电子显微镜下发现所得的aCgn聚集体是可溶的并且显示出半柔性的丝状聚集体形态。另外，通过刚果红结合和X射线衍射均证明丝状聚集体具有淀粉样蛋白特性。肽级氢交换（HX）分析表明，由三个肽段（39-46、51-64和106-114）组成的天然β-表层被掩埋重组为aCgn聚集体的跨β淀粉样蛋白核心，至少类似于50％的序列在集合体中采用无序结构。此外，观察到的三个报告的肽（65-102、160-180和229-245）的等摩尔双峰HX标记分布表明aCgn聚集物中两个分子构象的异质组装。这证明了淀粉样蛋白典型的扩展的β-折叠相互作用足够强，以至于即使在有利于胶体稳定性的条件下，相对较小比例的多肽序列也可以驱动丝状聚集体的形成。

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