VIB Switch Laboratory, VIB, Leuven, Belgium.
Curr Top Med Chem. 2012;12(22):2470-8. doi: 10.2174/1568026611212220003.
Most protein sequences contain one or several short aggregation prone regions (APR) that can nucleate protein aggregation. Under normal conditions these APRs are protected from aggregation by protein interactions or because they are buried in the hydrophobic core of native protein domains. However, mutation, physiological stress or age-related disregulation of protein homeostasis increases the probability that aggregation-nucleating regions become solvent exposed. Aggregation then results from the self-assembly of APRs into β-structured agglomerates that vary from small soluble oligomeric assemblies to large insoluble inclusions containing thousands of molecules. The functional effects of APR-driven aggregation are diverse and protein-specific leading to distinct disease phenotypes ranging from neurodegeneration to cancer. On a cellular and physiological level both wild type loss-of-function as well as aggregation-dependent gain-of-function effects have been shown to contribute to disease. Several molecular mechanism have been proposed to contribute to gain-of-function activity of protein aggregates including cellular membrane disregulation, saturation of the protein quality control machinery or the ability of aggregates to engage non-native interactions with proteins and nucleic acids. These different mechanisms will all, to some extent, contribute to gain-of-function as in essence they all contribute to the rewiring of the cellular interactome by aggregation-specific interactions, resulting for instance in the pronounced neurotoxicity of TDP43 aggregates by the sequestration of RNA molecules or the promotion of cell proliferation by the entrapment of homologous tumor suppressor proteins in p53 aggregates in cancer. In this review we discuss the mechanism of APR driven aggregation and how APRs contribute to modifying the cellular interactome by recruiting both misfolded as well as active proteins thereby inhibiting or activating specific cellular functions. Finally, we discuss the ubiquity of APRs in protein sequences and how selective pressure shaped protein sequences to minimize APR aggregation.
大多数蛋白质序列包含一个或多个短的易于聚集的区域 (APR)，这些区域可能引发蛋白质聚集。在正常情况下，这些 APR 受到蛋白质相互作用的保护，或者因为它们埋藏在天然蛋白质结构域的疏水区内。然而，突变、生理应激或与年龄相关的蛋白质内稳态失调会增加 APR 成为溶剂暴露的可能性。然后，聚集是由 APR 自组装成β-结构聚集体引起的，这些聚集体的大小从小的可溶性寡聚体组装体到含有数千个分子的大的不溶性内含物不等。APR 驱动的聚集的功能影响是多样化的，并且是蛋白质特异性的，导致从神经退行性变到癌症的不同疾病表型。在细胞和生理水平上，野生型丧失功能以及聚集依赖性获得功能的影响都被证明有助于疾病的发生。已经提出了几种分子机制来解释蛋白质聚集体的获得功能活性，包括细胞膜失调、蛋白质质量控制机制的饱和，或者聚集体与蛋白质和核酸发生非天然相互作用的能力。这些不同的机制在某种程度上都有助于获得功能，因为它们本质上都有助于通过聚集特异性相互作用重新布线细胞相互作用组，例如，TDP43 聚集体通过隔离 RNA 分子导致明显的神经毒性，或者通过将同源肿瘤抑制蛋白困在 p53 聚集体中促进癌细胞增殖。在这篇综述中，我们讨论了 APR 驱动聚集的机制，以及 APR 如何通过招募错误折叠和活性蛋白来改变细胞相互作用组，从而抑制或激活特定的细胞功能。最后，我们讨论了 APR 在蛋白质序列中的普遍性，以及选择压力如何塑造蛋白质序列以最小化 APR 聚集。
