The importance of sequence diversity in the aggregation and evolution of proteins
The importance of sequence diversity in the aggregation and evolution of proteins
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DOI：
10.1038/nature04195
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发表时间：
2005-12-08
期刊：
影响因子：
64.8
通讯作者：
Dobson, CM
中科院分区：
文献类型：
--
作者：
Wright, CF;Teichmann, SA;Dobson, CM
蛋白质的不正确折叠会导致聚集和淀粉样蛋白形成，与一系列高度衰弱的疾病有关(1,2)，包括阿尔茨海默氏病和迟发性糖尿病。如何在生命系统中通常避免不需要的蛋白质关联的问题在多结构域蛋白质的进化背景下尤其重要，多结构域蛋白质占所有真核蛋白质的 70% 以上(3)，其中每个结构域附近的有效局部蛋白质浓度非常高。在这里，我们描述了免疫球蛋白结构域的多结构域蛋白质构建体的聚集动力学以及不同同源结构域聚集在一起的能力。我们表明这些蛋白质的聚集是一个特定的过程，并且不同结构域之间的共聚集效率随着序列同一性的降低而显着降低。因此，虽然具有超过约70%同一性的免疫球蛋白结构域极易发生共聚集，但具有低于30-40%序列同一性的免疫球蛋白结构域不能检测到相互作用。对大型多结构域蛋白中连续同源结构域的生物信息学分析表明，此类结构域几乎完全具有低于 40% 的序列同一性，换句话说，低于共聚集可能有效的水平。我们认为，如此低的序列同一性可能在保护蛋白质免遭错误折叠和聚集方面发挥关键和普遍的作用。
Incorrect folding of proteins, leading to aggregation and amyloid formation, is associated with a group of highly debilitating medical conditions(1,2) including Alzheimer's disease and late-onset diabetes. The issue of how unwanted protein association is normally avoided in a living system is particularly significant in the context of the evolution of multidomain proteins, which account for over 70% of all eukaryotic proteins(3), where the effective local protein concentration in the vicinity of each domain is very high. Here we describe the aggregation kinetics of multidomain protein constructs of immunoglobulin domains and the ability of different homologous domains to aggregate together. We show that aggregation of these proteins is a specific process and that the efficiency of coaggregation between different domains decreases markedly with decreasing sequence identity. Thus, whereas immunoglobulin domains with more than about 70% identity are highly prone to coaggregation, those with less than 30 - 40% sequence identity do not detectably interact. A bioinformatics analysis of consecutive homologous domains in large multidomain proteins shows that such domains almost exclusively have sequence identities of less than 40%, in other words below the level at which coaggregation is likely to be efficient. We propose that such low sequence identities could have a crucial and general role in safeguarding proteins against misfolding and aggregation.