Mechanisms of Protein Aggregation
Protein aggregates represent an energetically stable, but non-functional alternative to the normal, functional, and soluble state of most proteins. In the context of human disease, aggregation occurs as proteins misfold or misassemble outside or inside the cell. Extracellular aggregation can lead to toxic forms such as amyloid fibrils that are associated with neurological conditions such as Alzheimer’s and Parkinson’s disease. Intracellular aggregation places stress on the normal quality control machinery of the cell and in some cases can disrupt cell function as improperly folded proteins aggregate and overwhelm the system. Biotherapeutics, many of which are proteins, can also aggregate upon long-term storage or stress (e.g., heat, oxidation), leading to loss of efficacy or even undesired immune responses. A better understanding of the underlying features that influence, control, and prevent protein aggregation is essential to improve and protect human health.
Protein aggregation is being studied from many vantage points using a variety of established and new tools. One area of interest is elucidating the molecular details of proteins that aggregate as part of human diseases. As an example, the pathways by which serpins misfold and form the aggregates associated with serpinopathies are being interrogated with biophysical methods (Gierasch, Gershenson) and mammalian cell culture models (Hebert).
Fundamental questions about protein folding and aggregation are under study using powerful biophysical methods (Gierasch). A myloid formation, which is a special type of aggregation associated with diseases such as Alzheimer’s, is being examined with a focus on the early stages of this process (Vachet) so that it can be effectively interrupted.
Members of the research theme are also seeking to understand the quality control machinery that prevents aberrant aggregation. Studies of the mammalian secretory pathway (Hebert) provide insight into processes that prevent intracellular aggregation and recognize and remove or repair misfolded proteins, while a variety of biochemical, cell and structural biology techniques are being used to understand the molecular machines that degrade damaged or improperly folded proteins (Chien). Another focus is assessing the changes to protein therapeutics that can occur during long-term storage or after exposure to heat, oxidation, or other abnormal storage conditions.
New tools based on mass spectrometry (Kaltashov, Vachet) are being developed to elucidate the covalent and non-covalent changes that trigger aggregation of protein therapeutics.