Cytotoxicity of Aberrant Proteins

Abstract

A wide range of diseases are caused by the generation of aberrant proteins that for one reason or another are not functionally equivalent to the normal version. Here, we consider the basic cellular principles that govern the generation of aberrant proteins, their normal metabolism and in the case of disease, their adverse effects on cellular function. Key concepts The organization of proteins inside cells is highly regulated at many levels. Proteins that are not folded correctly or not trafficked to their intended destination are aberrant and have the potential to cause cellular dysfunction. Numerous quality control systems constantly detect and degrade aberrant proteins. Failure to either recognize or promptly degrade aberrant proteins can lead to their accumulation, and in some cases, their aggregation. Misfolded or mislocalized proteins can interact inappropriately with other cellular factors to cause toxicity. Most diseases of protein misfolding probably have multiple mechanisms that operate simultaneously to cause pathology.

Determining the Conformational Stability of a Protein from Urea and Thermal Unfolding Curves

“…These methods are especially useful to quantitate changes in stability when protein variants are made with the aim of studying the forces that affect stability. For a discussion of these types of forces, see Dill (1990), Makhatadze and Privalov (1995), Fersht (1999), Pace et al (2009), andPace et al (2011).…”