Meisl Georg, Xu Catherine K, Taylor Jonathan D, Michaels Thomas C T, Levin Aviad, Otzen Daniel, Klenerman David, Matthews Steve, Linse Sara, Andreasen Maria, Knowles Tuomas P J
Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Sci Adv. 2022 Aug 12;8(32):eabn6831. doi: 10.1126/sciadv.abn6831.
Fibrillar protein aggregates are a hallmark of a range of human disorders, from prion diseases to dementias, but are also encountered in several functional contexts. Yet, the fundamental links between protein assembly mechanisms and their functional or pathological roles have remained elusive. Here, we analyze the aggregation kinetics of a large set of proteins that self-assemble by a nucleated-growth mechanism, from those associated with disease, over those whose aggregates fulfill functional roles in biology, to those that aggregate only under artificial conditions. We find that, essentially, all such systems, regardless of their biological role, are capable of self-replication. However, for aggregates that have evolved to fulfill a structural role, the rate of self-replication is too low to be significant on the biologically relevant time scale. By contrast, all disease-related proteins are able to self-replicate quickly compared to the time scale of the associated disease. Our findings establish the ubiquity of self-replication and point to its potential importance across aggregation-related disorders.
纤维状蛋白质聚集体是一系列人类疾病的标志，从朊病毒病到痴呆症，但在一些功能环境中也会出现。然而，蛋白质组装机制与其功能或病理作用之间的基本联系仍然难以捉摸。在这里，我们分析了大量通过成核生长机制自组装的蛋白质的聚集动力学，这些蛋白质包括与疾病相关的蛋白质、其聚集体在生物学中发挥功能作用的蛋白质，以及仅在人工条件下聚集的蛋白质。我们发现，基本上，所有这些系统，无论其生物学作用如何，都能够自我复制。然而，对于已经进化以发挥结构作用的聚集体来说，自我复制的速度太低，在生物学相关的时间尺度上不显著。相比之下，与所有疾病相关的蛋白质相比相关疾病的时间尺度能够快速自我复制。我们的发现确立了自我复制的普遍性，并指出了其在与聚集相关的疾病中的潜在重要性。
