A recent paper published in Science may change how we think about how protein folding in its endogenous context. For the past 50 years, the principles by which proteins unfold and refold have been studied largely using purified recombinant substrates. Under these experimental conditions, however, it has been extraordinarily difficult to examine how a protein folds in its native environment. To address this question, the Skach Lab developed a novel technique that uses fluorescence resonance energy transfer (FRET) to show that folding events are carefully choreographed during synthesis in the cell. Some events are actively delayed, while others are enhanced. These findings show that the final structure of proteins is precisely tuned by cellular machinery–and more importantly, they challenge almost 50 years of basic dogma, setting the stage to examine folding in a more holistic manner that takes into account environmental factors.
These findings have important health implications. Surprisingly large numbers of rare diseases are caused by inherited mutations that disrupt protein folding. One example is cystic fibrosis, a lethal disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. About 70% of those with cystic fibrosis harbor a 3 base pair deletion that results in CFTR misfolding and premature degradation. Kim and colleagues provide the first detailed analysis of how this region of CFTR actually folds–and they also show that a critical step in the pathway can occur only while the nascent protein is being synthesized and attached to the ribosome. CFTR folding is also linked to the rate of protein synthesis, which is in turn controlled by mRNA codon usage and the availability of specific transfer RNAs. Thus, they show that both folding and misfolding are integrated into a wide cellular context, not only in disease but also in normal function.
These results have implications for a broad spectrum of disease, ranging from cystic fibrosis to Parkinsons disease, Alzheimer’s disease, prion diseases, hypercholesterolemia, and more, all of which are characterized by protein folding disorders. Beyond the implications for these basic disease pathways, these findings also provide foundational insight into an entirely new class of drugs such as those that act by correcting the underlying defects in the folding of CFTR.
The paper, “Translational tuning optimizes nascent protein folding in cells”, was published in Science on April 24, 2015. The authors are Soo Jung Kim, Jae Seok Yoon, Hideki Shishido, Zhongying Yang, LeeAnn Rooney, Jose Barral, and William Skach, professor of biochemistry, OHSU School of Medicine and VP for Research Affairs, Cystic Fibrosis Foundation.