The Three Functional States of Proteins: Structured, Intrinsically Disordered, and Phase Separated

Traditionally, different states of proteins have been defined based on their structures and functions. However, it is becoming increasingly clear that these criteria may not be sufficient to capture the complex properties of these molecules and that definitions based on thermodynamics and kinetics could be more appropriate. Emerging evidence indicates that under physiological conditions, most proteins can sample the native, droplet, and amyloid states. These states contribute to different cellular functions in accordance with their physical and structural properties. The native monomeric or oligomeric state of a protein is typically the most frequently observed state under cellular conditions. The biological functions of proteins are associated with this native state. Proteins in this functional state can be highly structured or intrinsically disordered (i.e., exist as highly dynamic structural ensembles of interconverting conformations), or they can combine features of order and disorder. The amyloid state with its cross- structure is a solid-like condensed state that is thermodynamically stable at the cellular concentrations of proteins, and therefore its formation tends to be irreversible. Although many known examples of amyloids are related to the pathogenesis of various human diseases, functional amyloids are found in all kingdoms of life. The droplet or phase-separated state is a liquid-like condensed state formed by the non-stoichiometric assembly of protein molecules, often via interaction with nucleic acids. This is the functional state of many membrane-less organelles, which are now considered major organizing elements of intracellular space. This book provides comprehensive coverage of these three protein states and their thermodynamics and kinetic properties. The book also considers their interactions and discuss how their internal organization as individual molecules and their collective organization as molecular assemblies are stabilized. It also discusses how these states are formed and examines the cellular functions associated with the specific states.