School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Himachal Pradesh 175005, India.
Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA.
Biomolecules. 2020 May 21;10(5):796. doi: 10.3390/biom10050796.
The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure-function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.
26S 蛋白酶体是一个由至少 33 种不同亚基和许多其他成分组成的大型 (~2.5 MDa) 蛋白复合物，这些成分共同构成了泛素蛋白酶体系统 (UPS)，这是一种细胞内依赖于 ATP 的蛋白质降解系统。UPS 是细胞内蛋白质监控机制的重要组成部分，其功能障碍会导致癌症、神经退行性疾病和免疫性疾病。重要的是，蛋白质的功能和调节受有序区域、固有无序蛋白质区域 (IDPR) 和分子识别特征 (MoRF) 的组合控制。UPS 成分的结构-功能关系尚未完全确定；因此，在这项研究中，我们对该途径的潜在神经退行性疾病和抗癌靶点进行了功能固有无序和 MoRF 分析。我们的报告表明，几个 UPS 蛋白中存在显著的固有无序和基于无序的结合区域，如额外蛋白酶体多泛素受体 (UBQLN1 和 UBQLN2)、蛋白酶体相关多泛素受体 (ADRM1 和 PSMD4)、去泛素化酶 (DUBs) (ATXN3 和 USP14) 和泛素化酶 (E2 (UBE2R2) 和 E3 (STUB1) 酶)。我们相信这项研究将对这些蛋白质不同区域的构象特异性作用产生影响。这将有助于更好地理解 UPS 相关疾病的分子基础。
