Abstract
Four decades of proteasome research have yielded extensive information on ubiquitin-dependent proteolysis. The archetype of proteasomes is a 20S barrel-shaped complex that does not rely on ubiquitin as a degradation signal but can degrade substrates with a considerable unstructured stretch. Since roughly half of all proteasomes in most eukaryotic cells are free 20S complexes, ubiquitin-independent protein degradation may coexist with ubiquitin-dependent degradation by the highly regulated 26S proteasome. This article reviews recent advances in our understanding of the biochemical and structural features that underlie the proteolytic mechanism of 20S proteasomes. The two outer α-rings of 20S proteasomes provide a number of potential docking sites for loosely folded polypeptides. The binding of a substrate can induce asymmetric conformational changes, trigger gate opening, and initiate its own degradation through a protease-driven translocation mechanism. Consequently, the substrate translocates through two additional narrow apertures augmented by the β-catalytic active sites. The overall pulling force through the two annuli results in a protease-like unfolding of the substrate and subsequent proteolysis in the catalytic chamber. Although both proteasomes contain identical β-catalytic active sites, the differential translocation mechanisms yield distinct peptide products. Nonoverlapping substrate repertoires and product outcomes rationalize cohabitation of both proteasome complexes in cells.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
After entering the gated channel into the 20S proteasome, substrates first traverse an antechamber defined by the α-subunits and only enter through a ~2.5nm diameter aperture defined by the β-annulus into the central proteolytic chamber (Figure 3B)
In contrast to primordial 20S proteasomes where all 14 β-subunits are catalytically active, it is possible that this “proteolytic gap” affords for partial cleavage of the substrates and generation of slightly longer peptide products that retain sequence information for downstream signaling pathways
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Archaea and some bacteria have 20S proteasomes alongside other ATP-dependent proteases, which supports the idea of the 20S complex being a primordial protein-degrading machine [15] These simple 20S proteasomes are made up of 14 copies of α and β subunits each [16,17], intermittently aided by a loosely associated homomeric ring of ATPases [15,18,19]. Any physiological condition that demands an alteration to the proteome or impairs emergency proteasome under cellular stress, for example oxidative stress or hypoxic protein function requires enhanced capacity to remove the unnecessary load. Any physiological condition that demands an alteration to the proteome or impairs proteins and inevitably affect the ubiquitin–proteasome machinery These stress conditions can requires lead to 26Senhanced accumulation in storage its disassembly [1,2,65], protein function capacity togranules remove[62,63,64], the unnecessary load. 20S cryo‐EM structure [49]
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