Buneeva Olga A, Kopylov Arthur T, Medvedev Alexei E
Institute of Biomedical Chemistry, Moscow, 119121, Russia.
Biochemistry (Mosc). 2023 Mar;88(3):319-336. doi: 10.1134/S0006297923030033.
Proteasomes are highly conserved multienzyme complexes responsible for proteolytic degradation of the short-lived, regulatory, misfolded, and damaged proteins. They play an important role in the processes of brain plasticity, and decrease in their function is accompanied by the development of neurodegenerative pathology. Studies performed in different laboratories both on cultured mammalian and human cells and on preparations of the rat and rabbit brain cortex revealed a large number of proteasome-associated proteins. Since the identified proteins belong to certain metabolic pathways, multiple enrichment of the proteasome fraction with these proteins indicates their important role in proteasome functioning. Extrapolation of the experimental data, obtained on various biological objects, to the human brain suggests that the proteasome-associated proteins account for at least 28% of the human brain proteome. The proteasome interactome of the brain contains a large number of proteins involved in the assembly of these supramolecular complexes, regulation of their functioning, and intracellular localization, which could be changed under different conditions (for example, during oxidative stress) or in different phases of the cell cycle. In the context of molecular functions of the Gene Ontology (GO) Pathways, the proteins of the proteasome interactome mediate cross-talk between components of more than 30 metabolic pathways annotated in terms of GO. The main result of these interactions is binding of adenine and guanine nucleotides, crucial for realization of the nucleotide-dependent functions of the 26S and 20S proteasomes. Since the development of neurodegenerative pathology is often associated with regioselective decrease in the functional activity of proteasomes, a positive therapeutic effect would be obviously provided by the factors increasing proteasomal activity. In any case, pharmacological regulation of the brain proteasomes seems to be realized through the changes in composition and/or activity of the proteins associated with proteasomes (deubiquitinase, PKA, CaMKIIα, etc.).
蛋白酶体是高度保守的多酶复合体，负责对寿命短暂、具有调节作用、错误折叠和受损的蛋白质进行蛋白水解降解。它们在大脑可塑性过程中发挥重要作用，其功能下降伴随着神经退行性病变的发展。在不同实验室对培养的哺乳动物和人类细胞以及大鼠和兔脑皮质制剂进行的研究揭示了大量与蛋白酶体相关的蛋白质。由于鉴定出的蛋白质属于特定的代谢途径，这些蛋白质在蛋白酶体组分中的多重富集表明它们在蛋白酶体功能中起重要作用。将在各种生物对象上获得的实验数据外推至人类大脑表明，与蛋白酶体相关的蛋白质至少占人类大脑蛋白质组的28%。大脑的蛋白酶体相互作用组包含大量参与这些超分子复合体组装、其功能调节和细胞内定位的蛋白质，这些蛋白质在不同条件下（例如在氧化应激期间）或细胞周期的不同阶段可能会发生变化。在基因本体论（GO）途径的分子功能背景下，蛋白酶体相互作用组的蛋白质介导了根据GO注释的30多种代谢途径的组分之间的相互作用。这些相互作用的主要结果是腺嘌呤和鸟嘌呤核苷酸的结合，这对于26S和20S蛋白酶体的核苷酸依赖性功能的实现至关重要。由于神经退行性病变的发展通常与蛋白酶体功能活性的区域选择性降低有关，因此增加蛋白酶体活性的因素显然会产生积极的治疗效果。无论如何，大脑蛋白酶体的药理学调节似乎是通过与蛋白酶体相关的蛋白质（去泛素酶、蛋白激酶A、钙/钙调蛋白依赖性蛋白激酶IIα等）的组成和/或活性变化来实现的。
