Chapter 6 - Protein destabilization and degradation as a mechanism for hereditary disease

Abstract

In order to be functional, most proteins must fold into a well-defined and stable three-dimensional structure. Evolution, however, selects for function and not directly for stability, and consequently, the native, biologically active state is often only marginally stable under physiological conditions. Accordingly, as a result of mutations or stress conditions, proteins are prone to become structurally destabilized or locked in misfolded conformations. Since such protein species can be toxic and form various aggregates, all cells have evolved a protein quality control (PQC) system that constantly scans the intracellular space for nonnative proteins. Upon encountering such proteins, molecular chaperones and proteases of the PQC system ensure their rapid elimination from the cell, via either refolding or degradation. A number of studies have linked the PQC system with disease. For instance, a defective PQC system may lead to accumulation of toxic protein species that can cause disease, including numerous neurodegenerative disorders. Conversely, in cases where a disease-linked mutation causes a structural destabilization of the germline-encoded protein, an overmeticulous PQC system can lead to hereditary diseases, including cystic fibrosis, diabetes, phenylketonuria, and Lynch syndrome. Here, we briefly summarize the molecular mechanisms of the PQC system and its importance for various genetic disorders.