Biological Roles of Protein Kinetic Stability.

A protein's stability may range from nonexistent, as in the case of intrinsically disordered proteins, to very high, as indicated by a protein's resistance to degradation, even under relatively harsh conditions. The stability of this latter group is usually under kinetic control because of a high activation energy for unfolding that virtually traps the protein in a specific conformation, thereby conferring resistance to proteolytic degradation and misfolding aggregation. The usual outcome of kinetic stability is a longer protein half-life. Thus, the protective role of protein kinetic stability is often appreciated, but relatively little is known about the extent of biological roles related to this property. In this Perspective, we will discuss several known or putative biological roles of protein kinetic stability, including protection from stressors to avoid aggregation or premature degradation, achieving long-term phenotypic change, and regulating cellular processes by controlling the trigger and timing of molecular motion. The picture that emerges from this analysis is that protein kinetic stability is involved in a myriad of known and yet to be discovered biological functions via its ability to confer degradation resistance and control the timing, extent, and permanency of molecular motion.

Increased levels of hyper-stable protein aggregates in plasma of older adults.

Proteins that misfold into hyper-stable/degradation-resistant species during aging may accumulate and disrupt protein homeostasis (i.e., proteostasis), thereby posing a survival risk to any organism. Using the method diagonal two-dimensional (D2D) SDS-PAGE, which separates hyper-stable SDS-resistant proteins at a proteomics level, we analyzed the plasma of healthy young (<30 years) and older (60-80 years) adults. We discovered the presence of soluble SDS-resistant protein aggregates in the plasma of older adults, but found significantly lower levels in the plasma of young adults. We identified the inflammation-related chaperone protein haptoglobin as the main component of the hyper-stable aggregates. This observation is consistent with the growing link between accumulations of protein aggregates and aging across many organisms. It is plausible higher amounts of SDS-resistant protein aggregates in the plasma of older adults may reflect a compromise in proteostasis that may potentially indicate cellular aging and/or disease risk. The results of this study have implications for further understanding the link between aging and the accumulation of protein aggregates, as well as potential for the development of aging-related biomarkers. More broadly, this novel application of D2D SDS-PAGE may be used to identify, quantify, and characterize the degradation-resistant protein aggregates in human plasma or any biological system.