Abstract
The ubiquitin-proteasome system (UPS) is responsible for the bulk of protein degradation in eukaryotic cells, but the factors that cause different substrates to be unfolded and degraded to different extents are still poorly understood. We previously showed that polyubiquitinated substrates were degraded with greater processivity (with a higher tendency to be unfolded and degraded than released) than ubiquitin-independent substrates. Thus, even though ubiquitin chains are removed before unfolding and degradation occur, they affect the unfolding of a protein domain. How do ubiquitin chains activate the proteasome’s unfolding ability? We investigated the roles of the three intrinsic proteasomal ubiquitin receptors - Rpn1, Rpn10 and Rpn13 - in this activation. We find that these receptors are required for substrate-mediated activation of the proteasome’s unfolding ability. Rpn13 plays the largest role, but there is also partial redundancy between receptors. The architecture of substrate ubiquitination determines which receptors are needed for maximal unfolding ability, and, in some cases, simultaneous engagement of ubiquitin by multiple receptors may be required. Our results suggest physical models for how ubiquitin receptors communicate with the proteasomal motor proteins.
Highlights
IntroductionShort-lived transcription factors and other regulatory proteins are all degraded by the Ubiquitin-Proteasome System (UPS) in eukaryotic cells[1,2]
Misfolded and damaged proteins, short-lived transcription factors and other regulatory proteins are all degraded by the Ubiquitin-Proteasome System (UPS) in eukaryotic cells[1,2]
The proteasomal ATPases begin pulling on the substrate, leading to first the removal of the polyubiquitin chain by the Rpn[11] deubiquitinase[17,18], and subsequently to the unfolding of the substrate protein and its translocation into the 20S core particle, where it is hydrolyzed into short peptides[19] (Fig. 1)
Summary
Short-lived transcription factors and other regulatory proteins are all degraded by the Ubiquitin-Proteasome System (UPS) in eukaryotic cells[1,2]. K63-linked chains, in contrast, are typically used in cellular trafficking and signaling, for certain substrates and under certain conditions they can function in proteasomal degradation[6,7,8]. Yeast with all three receptors mutated remain viable, and a proteasome that is mutant for all receptors is still capable of degrading some proteins, suggesting the potential for additional receptors that have yet to be discovered[14] It remains unclear why the proteasome contains such an array of ubiquitin-binding functionalities as well as what additional roles different ubiquitin receptors may play in the overall mechanism of protein degradation by the proteasome. The proteasomal ATPases begin pulling on the substrate, leading to first the removal of the polyubiquitin chain by the Rpn[11] deubiquitinase[17,18], and subsequently to the unfolding of the substrate protein and its translocation into the 20S core particle, where it is hydrolyzed into short peptides[19] (Fig. 1)
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