Theodicy: another error correction system (Introduction)

by David Turell @, Friday, August 27, 2021, 15:01 (57 days ago) @ David Turell

Improper production of proteins is discarded:

"The assembly of multiprotein complexes inside the cell requires each subunit to be produced at a defined level relative to its partners. Imbalances in subunit synthesis are inevitable, necessitating the elimination of unassembled intermediates. Zavodszky et al. found that a ubiquitin ligase called HERC1 is responsible for marking certain assembly intermediates of the proteasome for degradation. HERC1 finds these intermediates by recognizing a proteasome assembly factor that normally dissociates when assembly is complete. A point mutation in HERC1 that impairs its ability to recognize proteasome assembly intermediates causes neurodegeneration in mice, highlighting the importance of this quality control pathway.

"In eukaryotic cells, half of all proteins function as subunits within multiprotein complexes. Imbalanced synthesis of subunits leads to unassembled intermediates that must be degraded to minimize cellular toxicity. Here, we found that excess PSMC5, a subunit of the proteasome base, was targeted for degradation by the HERC1 ubiquitin ligase in mammalian cells. HERC1 identified unassembled PSMC5 by its cognate assembly chaperone PAAF1. Because PAAF1 only dissociates after assembly, HERC1 could also engage later assembly intermediates such as the PSMC4-PSMC5-PAAF1 complex. A missense mutant of HERC1 that causes neurodegeneration in mice was impaired in the recognition and ubiquitination of the PSMC5-PAAF1 complex. Thus, proteasome assembly factors can serve as adaptors for ubiquitin ligases to facilitate elimination of unassembled intermediates and maintain protein homeostasis."


Conclusions and perspective

"Unassembled subunits have long been appreciated to be quality-control targets for one of two reasons: either they misfold in the absence of assembly or the exposed assembly interface is recognized by quality-control factors. In both cases, exposed hydrophobic surfaces are thought to be the target for quality control. Our findings reveal a qualitatively different mechanism: Delayed assembly cues ubiquitin ligase recruitment using the associated assembly factor. A major advantage for the cell of such a kinetic competition mechanism is that recognition does not depend on potentially toxic misfolding or aggregation. Instead, a simple delay would be sufficient to trigger elimination of otherwise normal intermediates. By using an assembly factor to identify incomplete products, a ubiquitin ligase can potentially recognize multiple intermediates along the assembly pathway." (my bolds)

Comment: God's quality control. I like that as a title.

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