Proteasome Interactome and Its Role in the Mechanisms of Brain Plasticity

Abstract

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.).

Proteomic Profiling of Mouse Brain Pyruvate Kinase Binding Proteins: A Hint for Moonlighting Functions of PKM1?

“…PKM1 participates in interactions with proteasome subunits (PSMA6), known glycolytic proteins exhibiting moonlighting functions (ALDOA, GAPDH, and ENO1), and also with proteins involved in protein folding and chaperoning (HSP90AB1, HSPA8, and NPM1). Some of these interactions obviously reflect canonical functions of the glycolytic enzymes supporting proteasomes with additional energy resources and promoting maintenance of nucleotide-dependent functions of proteasomes [33]. The group of proteins involved in protein folding and chaperoning is particularly interesting.…”