Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Institutskiy Pereulok, 9, Dolgoprudny, 141700, Russia.
Institute of Cytology, Russian Academy of Sciences, Saint Petersburg, 194064, Russia.
Cell Mol Life Sci. 2023 Aug 27;80(9):269. doi: 10.1007/s00018-023-04897-3.
The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1702 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is however less than the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the used here aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels, revealing the importance of "structure-function continuum" in aging. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment has simultaneously high liquid-liquid phase separation (LLPS) probability, "nuclear" localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, and stem cells exhaustion. Intrinsic disorder, LLPS, and aggregation propensity should be considered as features that could be markers of pathogenic proteins. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss of function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down.
衰老的发展与关键细胞过程的破坏有关，这些过程表现为衰老的既定标志。无规卷曲蛋白质（IDPs）和无规卷曲区域（IDRs）没有稳定的三级结构，这使它们成为信号级联中的可配置枢纽，并调节许多过程，可能包括与衰老相关的过程。需要阐明 IDPs/IDRs 在衰老中的作用。从已建立的衰老数据库和实验研究中收集了 1702 种与衰老相关的蛋白质数据集。明显存在 IDPs/IDRs，约占衰老相关数据集的 36%，但低于整个人类蛋白质组的无序含量（约 40%）。这里使用的衰老蛋白质组的基因本体分析揭示了三分之一的与衰老相关的过程中存在丰富的 IDPs/IDRs，特别是在基因组调控中。与衰老相关的信号通路也在不同的层次结构上包含 IDPs/IDRs，揭示了“结构-功能连续体”在衰老中的重要性。蛋白质-蛋白质相互作用网络分析表明，存在于与不同衰老标志相关的不同簇中的 IDPs。具有 IDPs 富集的蛋白质簇同时具有高液-液相分离（LLPS）概率、“核”定位和与衰老标志相关的 DNA 相关功能，包括基因组不稳定性、端粒磨损、表观遗传改变和干细胞衰竭。固有无序、LLPS 和聚集倾向应被视为可能是致病蛋白质标志物的特征。总体而言，我们的分析表明 IDPs/IDRs 在与衰老相关的过程中发挥着重要作用，特别是在 DNA 功能的调节中。IDP 聚集可能导致功能丧失和毒性，这对细胞可能是极其有害的。基于结构的衰老分析和鉴定特别容易受到干扰的蛋白质，可以增强我们对衰老分子机制的理解，并为减缓衰老开辟新途径。
