20S proteasomes and protein degradation “by default”

Abstract

The degradation of the majority of cellular proteins is mediated by the proteasomes. Ubiquitin-dependent proteasomal protein degradation is executed by a number of enzymes that interact to modify the substrates prior to their engagement with the 26S proteasomes. Alternatively, certain proteins are inherently unstable and undergo "default" degradation by the 20S proteasomes. Puzzlingly, proteins are by large subjected to both degradation pathways. Proteins with unstructured regions have been found to be substrates of the 20S proteasomes in vitro and, therefore, unstructured regions may serve as signals for protein degradation "by default" in the cell. The literature is loaded with examples where engagement of a protein into larger complexes increases protein stability, possibly by escaping degradation "by default". Our model suggests that formation of protein complexes masks the unstructured regions, making them inaccessible to the 20S proteasomes. This model not only provides molecular explanations for a recent theoretical "cooperative stability" principle, but also provokes new predictions and explanations in the field of protein regulation and functionality.

Phosphorylation Regulates the Ubiquitin-independent Degradation of Yeast Pah1 Phosphatidate Phosphatase by the 20S Proteasome

“…Generally, the posttranslational modification of ubiquitination provides a signal and facilitates unfolding for degradation by the 26S proteasome (84 -86). However, proteins may also be subjected to proteasomal degradation through a ubiquitin-independent mechanism that is mediated by unfolded regions of the protein (79,87). Pah1 is identified as an unstable protein based on its primary structure (88), and the FoldIndex algorithm predicts that Pah1 is a highly unstructured protein with the exception of the conserved NLIP and HADlike domains.…”

The nature and extent of contributions by defective ribosome products to the HLA peptidome

“…This conclusion is based on the large contribution of subunits of large complexes, such as the ribosome and TCP-1 subunits, to the high DRiPs factor HLA peptidome. The excess production of such subunits can be caused by limiting production of one or more of the core subunits of the protein complexes (22,44) or in the case of the ribosomes, by limited availability of some ribosomal subunits (45) or rRNA ( Fig. 2 and Table 2).…”

Ubiquitin-independent p53 proteasomal degradation

“…The degradation of the stabilized protein requires the active process of polyubiquitination to become susceptible to proteasomal degradation. 5 …”