Nucleic Acids Roles in Protein Folding and Aggregation

PROJECT SUMMARY This project is to investigate how nucleic acids are involved in protein aggregation and folding. Protein misfolding and aggregation lead to many debilitating diseases including Alzheimer’s disease. We recently found that nucleic acids can have strong chaperone activity to prevent protein aggregation and aid protein folding. Given their preponderance in the cell and strong effects on protein folding and aggregation, it is highly likely that nucleic acids are important players in protein homeostasis. The work described in this proposal lays out studies to provide our first understanding of the basic principles by which nucleic acids modulate protein folding and aggregation, and thus protein homeostasis. Our current investigations are directed at addressing two critical aspects: 1) Understanding the roles of chaperone nucleic acids in the cell, and 2) Understanding the molecular mechanism of chaperone nucleic acids. These studies utilize an interdisciplinary approach combining molecular biology, biochemistry, biophysics, and bacterial genetics. Our preliminary data indicates that both the activities of nucleic acids to prevent and promote oligomerization are highly sequence dependent, and are especially encoded for by quadruplex structures. These results help explain the biophysical causes of several neurodegenerative diseases. This insight also gives us the opportunity to control and study protein aggregation using specific nucleic acid sequences and structures. Our preliminary data also indicates that quadruplex-containing chaperone sequences are also effective at improving the folding environment in E. coli. We are currently expanding these studies to known quadruplex structures with chaperone-like effects in the cell, and investigating the structural basis of chaperone activity. Together, these studies will lay the foundation for a new understanding of protein homeostasis and how it relates to nucleic acid biology. This information will be critical in the future to help combat myriad protein misfolding and aggregation diseases.