How do repetitive bacterial surface proteins avoid inter-domain aggregation?

蛋白质聚集与医学和生物技术有着广泛的相关性。聚集是阿尔茨海默病等临床疾病的基础，这些疾病正在给卫生服务带来越来越严重的负担。聚集也是蛋白质治疗药物生产、储存和应用的关键问题，无论是自然发生的还是使用新型合成支架生产的。一系列对聚集具有内在抵抗力的支架将为未来的生物学提供一个有价值的起点。当(正常埋藏的)蛋白质序列的区域暴露并相互作用时，聚集发生；聚集依赖于分子之间的高序列同一性和高浓度。因此，观察到多结构域蛋白中的相邻结构域通常有40%的序列一致性，这被解释为减少相邻的共价连接结构域之间聚集的进化反应。在JRP组研究的重复细菌表面蛋白中，蛋白质序列的同一性是高度相同的DNA重复的结果，DNA重复通过重组事件产生不同重复数的蛋白质为有机体提供潜在优势(一种潜在的免疫逃避机制)。然而，由此产生的蛋白质序列重复应该导致聚集。我们的新假说是，在重复的细菌蛋白质中，免疫逃避“赢”了，蛋白质聚集问题的新解决方案已经进化，并将在分离的区域中被检测到。初步工作支持这一假设。

Protein aggregation has wide relevance to medicine and biotechnology. Aggregation underlies clinical conditions such as Alzheimer's disease that are placing an increasingly severe burden on health services. Aggregation is also a key problem for production, storage and application of protein therapeutics whether naturally occurring or produced using novel synthetic scaffolds. A range of scaffolds with intrinsic resistance to aggregation would provide a valuable starting point for future biologics.Aggregation occurs when regions of (normally buried) protein sequence become exposed and interact; aggregation is dependent on high sequence identity between molecules and high concentration. Thus, the observation that adjacent domains in multi-domain proteins usually have <40% sequence identity has been interpreted as an evolutionary response to reduce aggregation between adjacent, covalently-linked domains. In repetitive bacterial surface proteins studied in the JRP group protein sequence identity is a result of highly identical DNA repeats that provide a potential advantage to the organism through recombination events that produce proteins with differing numbers of repeats (a potential immune evasion mechanism). However, the resultant protein sequence repetition should lead to aggregation. Our novel hypothesis is that, in repetitive bacterial proteins immune evasion "wins" and novel solutions to the protein aggregation problem have evolved and will be detectable in the isolated domains. Preliminary work supports this hypothesis.