Protein Folding in the Cell, from Atom to Organism

Proper cell function requires proper protein folding. Misfolding of specific proteins, caused either by mutation or environmental stress, underlies many human diseases, including cancer and diabetes and Parkinson’s, Huntington’s, and Alzheimer’s disease. Protein folding has been studied for decades in the test tube, initially spearheaded by the classical studies of Anfinsen and colleagues (1). Whereas in vitro studies continue to provide invaluable contributions toward developing a complete understanding of the fundamental physical and chemical forces that govern folding, there has been a concomitant and growing appreciation that the cellular environment presents unique challenges—as well as unique support systems—for protein folding that cannot be captured easily in testtube folding experiments. To understand how to keep cells healthy and how to correct diseased cells, we must understanding how proteins fold and misfold in vivo and define the mechanism of action of the cellular protein quality-control machinery (Fig. 1). Since 1990, the biennial FASEB Protein Folding in the Cell conference has been devoted to bridging the gap between our understanding of how proteins fold in the test tube and the consequences for the cell should they misfold. The Protein Folding in the Cell conference occupies a unique niche among summer conferences because of its ongoing success at drawing together cell biologists, geneticists, biophysicists, biochemists, theorists, and computational biologists to tackle the complex problems of protein folding and misfolding and their implications for human disease. The extent to which this meeting has played a central role in the development of the field cannot be overstated. Historically, biophysical chemists/theoreticians and cell biologists/geneticists who study protein folding rarely crossed paths. However, the complexity of the protein folding “problem” and the paucity of methods available to study it in detail require a deep and multidisciplinary attack. Recent progress has shown the value of this approach in tackling some of the major outstanding questions in the field. At the 2014 meeting, held July 20–25 at the Vermont Academy in Saxton’s River, VT, the nine sessions and one Keynote Address covered every aspect of the protein-folding problem and its consequences for proper cell function. The titles of the scientific sessions were: “Principles of Protein Folding,” “Functions of Chaperone Machines,” “Cellular Responses and Protein Biogenesis,” “Protein Folding and Trafficking Networks,” “Biology and Biophysics of Amyloids and Aggregation,” “Evolution of Proteins and Protein Machines,” “Protein Quality Control and Degradation,” “Stress Responses, Molecular Chaperones, and Signaling,” and “Protein Maturation and Folding Decisions.” In addition to the didactic sessions, another dynamic aspect of the conference was its three-poster sessions that featured 93 submitted abstracts. The meeting was attended by nearly 150 scientists from academia, industry, and publishing houses and began with a Keynote Lecture from Lila Gierasch (University of Massachusetts, Amherst). In her lecture, Dr. Gierasch elegantly illustrated the synergy created by combining in vitro and in vivo studies of protein folding, focusing on her recent nuclear magnetic resonance and other biophysical studies (3, 4) to understand the allosteric regulation of the heat shock protein (Hsp)70 class of molecular chaperones and the impact of our improved understanding of how misfolded proteins are routed through protein quality-control networks in vivo (5). Many of the scientific presentations were buoyed by recent methodological and conceptual advances, often