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

蛋白质聚集与医学和生物技术具有广泛的相关性。聚集是阿尔茨海默病等临床病症的基础，这些病症给卫生服务带来越来越严重的负担。聚集也是蛋白质治疗剂的生产、储存和应用的关键问题，无论是天然存在的还是使用新型合成支架生产的。一系列具有内在抗聚集性的支架将为未来的生物制剂提供有价值的起点。聚集发生在（通常被掩埋的）蛋白质序列区域暴露并相互作用时;聚集依赖于分子之间的高序列同一性和高浓度。因此，多结构域蛋白中相邻结构域通常具有<40%序列同一性的观察结果已被解释为减少相邻共价连接结构域之间聚集的进化反应。在JRP组中研究的重复细菌表面蛋白中，蛋白质序列同一性是高度相同的DNA重复序列的结果，这些重复序列通过重组事件为生物体提供了潜在的优势，这些重组事件产生了具有不同重复序列数量的蛋白质（潜在的免疫逃避机制）。然而，所得蛋白质序列重复应导致聚集。我们的新假设是，在重复的细菌蛋白质免疫逃避“赢”和新的解决方案的蛋白质聚集问题已经发展，并将在孤立的域中检测。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.