Role of Nucleic Acids as Chaperones in Protein Folding

Abstract

Many proteins have slow folding times in vitro that are physiologically untenable. To combat this challenge, ATP-dependent chaperonins are thought to possess the unique ability to catalyze protein folding. Performing quantitative model selection using protein folding and unfolding data, we here show that short nucleic acids containing Gquadruplex (G4) structure can also catalyze protein folding. Performing the experiments as a function of temperature demonstrates that the G4 reshapes the underlying driving forces of protein folding. To understand the structural basis of this catalytic activity, we introduce NMR method to solve the structures, at base-level resolution, of a multiconformer G4 with chaperone activity without chemical shift assignments. We then perform structure-function studies via mutation and chaperone assays to test the G4 properties important for chaperoning protein aggregation and protein folding. Together, our finding uncovers a previously underappreciated role for nucleic acid in proteostasis and offer a new strategy for studying nucleic acid structure-function relationship at residue level.