1. UPS-dependent strategies of protein quality control degradation.
- Author
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Müller, Leonie and Hoppe, Thorsten
- Abstract
Misfolded and unfolded proteins must be degraded by a specialized subset of E3 ubiquitin ligases responsible for selective degradation of damaged proteins. A diverse array of specialized E3 ubiquitin ligases with distinct but overlapping substrate recognition modes control intracellular protein quality control (PQC) degradation using both cytosolic and nuclear 26S proteasomes. Stress-induced perturbations in protein structure result in the exposure of hydrophobic sites, which are typically buried within the protein and consequently serve as PQC degrons. Recognition of PQC degrons relies on sensing the overall biophysical properties of the PQC degron motif. PQC degrons must be enriched in hydrophobic amino acids. The degradation of damaged proteins is critical for tissue integrity and organismal health because damaged proteins have a high propensity to form aggregates. E3 ubiquitin ligases are key regulators of protein quality control (PQC) and mediate the selective degradation of damaged proteins, a process termed 'PQC degradation' (PQCD). The degradation signals (degrons) that trigger PQCD are based on hydrophobic sites that are normally buried within the native protein structure. However, an open question is how PQCD-specialized E3 ligases distinguish between transiently misfolded proteins, which can be efficiently refolded, and permanently damaged proteins, which must be degraded. While significant progress has been made in characterizing degradation determinants, understanding the key regulatory signals of cellular and organismal PQCD pathways remains a challenge. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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