The folding pathway of alpha1-antitrypsin: avoiding the unavoidable

Understanding the folding pathway of α(1)-antitrypsin is of interest from both biomedical and fundamental molecular biology perspectives. The native fold of α(1)-antitrypsin is metastable, and therefore does not represent the most stable conformation that its primary sequence can adopt. More stable conformations are formed when the reactive center loop inserts, as the fourth strand, into the A β sheet. The accessibility of these alternative low-energy folds renders α(1)-antitrypsin susceptible to mutations that can result in dysfunction and pathology. Here, I review some of the literature from the past 20 years, which has examined how α(1)-antitrypsin folds and preserves its native metastable state. In addition, I look at the relationship between α(1)-antitrypsin folding and misfolding, and its role in disease.