Advantages of proteins being disordered

Abstract

The past decade has witnessed great advances in our understanding of protein structure-function relationships in terms of the ubiquitous existence of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). The structural disorder of IDPs/IDRs enables them to play essential functions that are complementary to those of ordered proteins. In addition, IDPs/IDRs are persistent in evolution. Therefore, they are expected to possess some advantages over ordered proteins. In this review, we summarize and survey nine possible advantages of IDPs/IDRs: economizing genome/protein resources, overcoming steric restrictions in binding, achieving high specificity with low affinity, increasing binding rate, facilitating posttranslational modifications, enabling flexible linkers, preventing aggregation, providing resistance to non-native conditions, and allowing compatibility with more available sequences. Some potential advantages of IDPs/IDRs are not well understood and require both experimental and theoretical approaches to decipher. The connection with protein design is also briefly discussed.

Keywords: drug design; flexibility; intrinsically disordered proteins; molecular recognition; protein design; protein function; protein-protein interaction.

Figure 1

Schematic diagrams illustrating nine possible advantages of IDPs/IDRs. (a) Economizing genome and protein resources: IDPs/IDRs use smaller protein size to afford the same interface area as ordered proteins. (b) Overcoming steric restrictions in binding: IDPs/IDRs can overcome steric restrictions in binding complexes by protruding into partners or wrapping around them in ways difficult for ordered proteins. (c) Achieving high specificity with low affinity: the highly complementary binding interfaces and the unfavorable conformational-entropy changes result in high specificity and low affinity. (d) Increasing binding rate: the kinetic advantage of IDPs in a binding process stems from a faster evolution step from the encounter complex and a slower escaping rate. (e) Facilitating posttranslational modifications: the conformational flexibility of IDPs/IDRs greatly facilitates the exposure of modification sites and their binding to modifying enzymes. (f) Enabling flexible linkers: the lack of ordered structures makes IDPs/IDRs dominant in flexible linkers of proteins which are obviously out of reach of ordered proteins. (g) Preventing aggregation: IDPs/IDRs possess favorable interactions with water and are inherently advantageous in preventing aggregation. (h) Providing resistance to non-native conditions: you cannot unfold what is already unfolded. (i) Allowing compatibility with more available sequences: the sequence space of IDPs/IDRs is expected to be larger than that of ordered proteins.

Figure 2

Distribution of binding affinity for (a) IDPs and (b) ordered proteins. The average values of logK_d are indicated by arrows. The analysis was based on the dataset compiled in Ref..

Figure 3

Schematic distribution of the expected packing density for IDPs/IDRs, ordered proteins and amyloid fibrils (adopted from Ref.101).

Figure 4

Schematic difference of the areas for IDPs and ordered proteins in the CH plot, where 〈H〉 and 〈Q〉 represent the fraction of hydrophobic and charged residues, respectively (modified from Ref.7).