Prediction of protein disorder based on IUPred

Abstract

Many proteins contain intrinsically disordered regions (IDRs), functional polypeptide segments that in isolation adopt a highly flexible conformational ensemble instead of a single, well-defined structure. Disorder prediction methods, which can discriminate ordered and disordered regions from the amino acid sequence, have contributed significantly to our current understanding of the distinct properties of intrinsically disordered proteins by enabling the characterization of individual examples as well as large-scale analyses of these protein regions. One popular method, IUPred provides a robust prediction of protein disorder based on an energy estimation approach that captures the fundamental difference between the biophysical properties of ordered and disordered regions. This paper reviews the energy estimation method underlying IUPred and the basic properties of the web server. Through an example, it also illustrates how the prediction output can be interpreted in a more complex case by taking into account the heterogeneous nature of IDRs. Various applications that benefited from IUPred to provide improved disorder predictions, complementing domain annotations and aiding the identification of functional short linear motifs are also described here. IUPred is freely available for noncommercial users through the web server (http://iupred.enzim.hu and http://iupred.elte.hu) . The program can also be downloaded and installed locally for large-scale analyses.

Keywords: globular domains; intrinsically disordered proteins; sequence-based prediction methods; short linear motifs; statistical potential.

Figure 1

Prediction of protein disorder using the IUPred web server for the human E3 ubiquitin‐protein ligase Mdm2. The IUPred output was generated using the long option. Various structural and functional elements are shown below the prediction profile: PTMs plot various phosphorylation sites collected from PhosphositePlus,78 known linear motif sites (SLiMs) are indicated with lighter (USP7 binding motifs) and darker orange boxes (nuclear import and export signals), the experimentally verified disordered region (DIS) form the DisProt database is shown as a red box, while regions found in the PBD are indicated as blue boxes. The three regions corresponding to globular domains are shaded. Most of the phosphorylation sites and linear motifs are located outside these regions and are believed to be largely disordered, in agreement with the IUPred prediction.