Expanding the Range of Protein Function at the Far End of the Order-Structure Continuum

Abstract

The traditional view of the structure-function paradigm is that a protein's function is inextricably linked to a well defined, three-dimensional structure, which is determined by the protein's primary amino acid sequence. However, it is now accepted that a number of proteins do not adopt a unique tertiary structure in solution and that some degree of disorder is required for many proteins to perform their prescribed functions. In this review, we highlight how a number of protein functions are facilitated by intrinsic disorder and introduce a new protein structure taxonomy that is based on quantifiable metrics of a protein's disorder. How Do Folded Proteins Differ from Unfolded Proteins?Proteins are dynamic biological molecules that are involved in virtually all cellular processes (1). At physiologic temperatures, proteins, like all polymers, sample a range of conformations that are a function of the macromolecular environment and the primary amino acid sequence of the protein in question. These considerations argue that a protein's "structure" is best described as a distribution over a conformational ensemble consisting of its thermally accessible structures. In this sense, a protein's conformational ensemble is intimately linked to its function.Typically, proteins are characterized as being either folded or unfolded. This classification scheme is best understood from an analysis of the corresponding conformational ensembles. Folded proteins have thermally accessible states that are similar to the ensemble average, whereas unfolded (or disordered) proteins sample a relatively vast array of dissimilar conformations during their biological lifetime (2). The native state of a folded protein corresponds to a global energy minimum that is well separated from a panoply of high energy states. The flexibility of a folded protein is related to the width of this minimum energy well (Fig. 1A). Disordered proteins, by contrast, have energy surfaces that contain many local energy minima that are separated by low barriers (on the order of k B T), thereby ensuring rapid transition between structurally dissimilar states during the protein's biological lifetime (Fig. 1B). The result is a heterogeneous ensemble of thermally accessible conformations.Although the terms folded and unfolded provide a useful framework for everyday discourse among specialists, classifying proteins in this way does not capture the rich and beautiful complexity that underlies protein structure (3-5). Indeed, a more accurate description would entail a characterization of a protein's conformational ensemble. The importance of this realization is highlighted by the fact that not all folded proteins are created equal; i.e. some "folded" ensembles are more heterogeneous than others. Similarly, disordered proteins may have ensembles that exhibit preferences for particular structural features. These considerations reinforce the notion that quantitative metrics describing the heterogeneity within a protein's ensemble would provide a more comprehensive assessment...

Epichromatin and chromomeres: a ‘fuzzy’ perspective

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Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

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“…[45][46][47][48][49][50][51][52][53] So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence-structurefunction relationship of proteins. 29,[54][55][56] Recently, the protein structure-function continuum concept was proposed by Uversky to illustrate the numerous biological functions of p53 through multiple proteoforms by various mechanisms and may be extended to many multi-function IDPs. 57 In this review, we will summarize recent advances of our understanding on the molecular recognition of IDPs/IDRs.…”

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