A cell is more than the sum of its (dilute) parts: A brief history of quinary structure

Most knowledge of protein structure and function is derived from experiments performed with purified protein resuspended in dilute, buffered solutions. However, proteins function in the crowded, complex cellular environment. Although the first four levels of protein structure provide important information, a complete understanding requires consideration of quinary structure. Quinary structure comprises the transient interactions between macromolecules that provides organization and compartmentalization inside cells. We review the history of quinary structure in the context of several metabolic pathways, and the technological advances that have yielded recent insight into protein behavior in living cells. The evidence demonstrates that protein behavior in isolated solutions deviates from behavior in the physiological environment.