Proteins are the molecules that do most of the work in our bodies. In any given cell, 10,000 unique proteins are expressed, giving rise to an overall 100 billion protein molecules that co-exist in each cell at any given time. Proteins are synthesized when they are needed to perform a task, then are being shuttled to their desired location within the cell, where they exert their job and finally degraded when the task is completed. If synthesis, localization or proteolysis are perturbed- a proteome chaos will occur. To maintain a healthy proteome, cells have developed protein quality control (PQC) pathways that monitor a proteins’s fate from synthesis to degradation. In fact, nearly 5% of mammalian genes are dedicated to PQC pathways and failure to maintain protein homeostasis (proteostasis) may result in human diseases, including inflammation, neurodegeneration and cancer.
Although the nature of the aberrant features recognized by most PQC is unknown, exposed hydrophobic residues in aberrant or mislocalized protein substrates is a key feature recognized by distinct PQC mechanisms. Hydrophobic residues are normally not exposed in the context of native protein conformation, as they are normally buried in a protein's core, at protein–protein interfaces, or are embedded within membranes. However, proteins’ structural integrity is continuously impaired by spontaneous cellular and environmental stresses. If not managed properly, exposed hydrophobicity can result in protein aggregation and subsequent reduced cell fitness. To prevent accumulation of toxic aggregates, cells are equipped with PQC mechanisms including chaperones and proteolytic pathways.
Despite the growing list of PQC substrates, it has been difficult to identify characteristics within abnormal proteins that are recognized by the different proteolytic pathways in the cell. Under normal physiological conditions, PQC systems typically handle only a small, random portion of the proteome that undergoes misfolding. Because of the difficulties in studying a small pool of proteins, PQC studies typically focus on a limited set of model misfolded or mislocalized substrate reporters and thus are often biased towards a narrow range of PQC pathways. We believe that the key for addressing open questions in PQC research is in coverage- if more diverse substrates are identified and studied in depth, the more we know about the process. To this end, we utilize system-level approaches together with genetics, biochemistry, cell biology and proteomic approaches to: (1) map distinct classes of hydrophobic degrons to elucidate the specificity of substrate selection; (2) identify novel E3 ligases playing a role in PQC pathways, explore redundancies among them and identify endogenous substrates proteome-wide; (3) investigate the physiological significance of PQC mechanisms. Altogether, this work will provide a comprehensive view of PQC pathways that recognize hydrophobicity. This is critical to further our understanding on how aberrant features in proteins are recognized and can provide valuable information for the development of new therapeutic intervention strategies that target abnormal proteins implicated in disease.
