Paradoxes and wonders of intrinsic disorder: Complexity of simplicity

Abstract

At first glance it may seem that intrinsically disordered proteins (IDPs) and IDP regions (IDPRs) are simpler than ordered proteins and domains on multiple levels. However, such multilevel simplicity equips these proteins with the ability to have very complex behavior.

Keywords: amino acid alphabet; complexity; functional complexity; intrinsically disordered proteins; structural content; structural heterogeneity.

Figure 1.

Peculiarities of the amino acid sequences of intrinsically disordered proteins. (A) Amino acid determinants defining structural and functional differences between the ordered and intrinsically disordered proteins. Fractional difference in the amino acid composition (compositional profile) between the typical IDPs from the DisProt database and a set of completely ordered proteins calculated for each amino acid residue. The fractional difference was evaluated as (C_DisProt-C_PDB)/C_PDB, where C_DisProt is the content of a given amino acid in a DisProt database, and C_PDB is the corresponding content in the dataset of fully ordered proteins from PDB select 25. Positive bars correspond to residues found more abundantly in IDPs, whereas negative bars show residues, in which IDPs are depleted. Amino acid types were ranked according to their decreasing disorder-promoting potential. (B) Evaluation of the charge-hydropathy space available for mouse proteins. In this plot, areas accessible to sequences encoding compact proteins and extended IDPs are separated by a set of boundaries described in the text.

Figure 2.

Structural heterogeneity of IDPs. Left side. Bi-colored, oversimplified representation of functional fully ordered proteins (blue) and fully disordered, completely structure-less proteins (red). Right side. A continuous emission spectrum illustrates exceptional structural heterogeneity of functional proteins ranging from fully ordered to completely structure-less proteins, with everything in between. Here, intrinsic disorder can have multiple faces, can affect different levels of protein structural organization, and whole proteins, or various protein regions can be disordered to a different degree.

Figure 3.

Energy landscape of ordered proteins and IDPs. A diagram showing the folding energy landscapes of a typical globular protein (A) and of a typical natively unfolded protein in the absence (B) or presence of different binding partners (C). These landscapes are depicted schematically in one-dimensional cross-section. Illustrative examples of corresponding structures are also shown. Reprinted from Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1834 (5), Uversky V.N., Unusual biophysics of intrinsically disordered proteins, Pages No. 932–951, Copyright (2013), with permission from Elsevier.