G-quadruplexes catalyze protein folding by reshaping the energetic landscape

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 G-quadruplex (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. As short nucleic acids can catalyze protein folding without the input of ATP, the ability of the cell to fold proteins is far higher than previously anticipated. Significance StatementHow folding of proteins occurs en masse in the cell is still a daunting unsolved problem. Many proteins have complicated and difficult folding trajectories, with in vitro folding times that are physiologically untenable. The acceleration of protein folding to physiologically relevant timescales is a biologically essential function thought to be accomplished by a small set of ATP-dependent chaperonins. In this work, we surprisingly show that small nucleic acid sequences containing G-quadruplexes can catalyze protein folding and reshape protein folding energy landscapes. As a result, the capacity for accelerating protein folding in the cells is far higher than previously suggested, potentially explaining the accommodation of large number of proteins with physiologically unreasonable folding times.