Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins

Abstract

Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. The major goals of this minireview are to show that, despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally heterogeneous, and can be considered an important part of the structure-function continuum. Furthermore, IDPs/IDPRs are everywhere, and are ubiquitously engaged in various interactions characterized by a wide spectrum of binding scenarios and an even wider spectrum of structural and functional outputs.

Keywords: complexity; dynamical system; intrinsically disordered protein; intrinsically disordered proteins; multifunctional protein; post-translational modification (PTM); posttranslational modification; protein folding; protein-protein interaction; structural heterogeneity.

FIGURE 1.

Different terms used in early literature to describe intrinsically disordered proteins.

FIGURE 2.

Similarity of the dynamic conformational behavior of an IDP (neuroligin cytoplasmic domain (1)) with the behavior of a typical chaotic system (the Lorenz attractor (2–4)). A, single molecule FRET analysis of the conformational dynamics of the neuroligin cytoplasmic domain (1). In the top plot, emissions of donor and acceptor are shown by green and red colors, respectively. A. U., arbitrary units. The bottom plot represents the time course of FRET efficiency. The protein clearly shows hopping behavior, possessing stochastic transitions between different FRET efficiency (E) values (1). B, the time course of one of the three variables in the Lorenz attractor (4), which is defined by a set of three nonlinear interdependent equations that were originally defined to describe the weather (2, 3). This variable changes stochastically, and its stochastic changes clearly resemble the time dependence of the FRET efficiency describing the conformational dynamics of the neuroligin cytoplasmic domain. In fact, similar to IDPs, this system is extremely sensitive to initial conditions (butterfly effect). C, the phase-space representation of the behavior of the variable in the Lorenz attractor (4). Here, the variable is plotted against its rate of change, generating the characteristic loops reflecting the presence of a strange attractor (2, 3). Note the resemblance of the shape of this plot to a butterfly. Such a shape indicates that the trajectories of the chaotic system converge onto an infinitely complicated shape, known as an attractor. Trajectories on this attractor that start close together diverge rapidly as time passes, but remain confined to the attractor (4).

FIGURE 3.

Schematic representation of a variety of folding transitions induced in IDPs/IDPRs by interaction with binding partners.

FIGURE 4.

Illustration of the stochastic machine. This figure shows a possible configuration for the complex involving axin, β-catenin, GSC-3β, and CKI-α. Axin is shown with color variation to make its pathway easier to follow. Ordered RGS (for regulator of G protein signaling) and DIX (for DIshevelled and aXin) domains are located at the N and C termini of axin, respectively. The dashed line corresponds approximately to the location of the Gly²⁹⁵–Ala⁵⁰⁰ disordered segment (60). Axin binds to CKI-α (at two separate sites), to GSK3β, and also to β-catenin. Because the β-catenin binding site of axin is located between the GSK3β and CKI-α interaction sites, and because the two binding sites with CKI-α may lead to the formation of a loop, β-catenin becomes close to both kinases. Hence, the formation of this β-catenin destruction complex pulls all the proteins together, and substantially raises their local concentrations. Because the phosphorylation sites are in a disordered region of β-catenin and because the various binding sites are all in a long disordered region in axin, random motions of these flexible regions can readily bring about the substrate-enzyme collisions needed for function. Reproduced with permission from Ref. . © 2013 John Wiley & Sons Inc.