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Review
. 2014 May;23(5):539-50.
doi: 10.1002/pro.2443. Epub 2014 Mar 17.

Advantages of proteins being disordered

Zhirong Liu  1 , Yongqi Huang
Affiliations
Review

Advantages of proteins being disordered

Zhirong Liu et al. Protein Sci. 2014 May.

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.

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Figures

Figure 1
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
Figure 2
Distribution of binding affinity for (a) IDPs and (b) ordered proteins. The average values of logKd are indicated by arrows. The analysis was based on the dataset compiled in Ref..
Figure 3
Figure 3
Schematic distribution of the expected packing density for IDPs/IDRs, ordered proteins and amyloid fibrils (adopted from Ref.101).
Figure 4
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).
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