Functional Segments on Intrinsically Disordered Regions in Disease-Related Proteins

Abstract

One of the unique characteristics of intrinsically disordered proteins (IPDs) is the existence of functional segments in intrinsically disordered regions (IDRs). A typical function of these segments is binding to partner molecules, such as proteins and DNAs. These segments play important roles in signaling pathways and transcriptional regulation. We conducted bioinformatics analysis to search these functional segments based on IDR predictions and database annotations. We found more than a thousand potential functional IDR segments in disease-related proteins. Large fractions of proteins related to cancers, congenital disorders, digestive system diseases, and reproductive system diseases have these functional IDRs. Some proteins in nervous system diseases have long functional segments in IDRs. The detailed analysis of some of these regions showed that the functional segments are located on experimentally verified IDRs. The proteins with functional IDR segments generally tend to come and go between the cytoplasm and the nucleus. Proteins involved in multiple diseases tend to have more protein-protein interactors, suggesting that hub proteins in the protein-protein interaction networks can have multiple impacts on human diseases.

Keywords: disease-related proteins; functional segments; intrinsically disordered regions; protein-protein interaction; subcellular location.

Figure 1

An example of possible protean segment (pProS) definition, illustrated by p53. The black line in the middle represents the amino acid chain, and the intrinsically disordered regions (IDR) predictions are presented below. Pink, orange, and red represent the results by MobiDB-lite, DISOPRED3, and DICHOT, respectively. Regions where any of the two methods predict IDR are defined as IDRs. The green bars represent pProSs, and the annotations defining pProS are shown above with residue numbers of the annotations. DBD: DNA-binding domain; Tet: Tetramerization domain.

Figure 2

The IDR ratios by disease category. The green, yellow, and blue bars represent the IDR fractions of the pProS-containing proteins, the non-pProS proteins, and the total proteins in each of the disease categories, respectively. The measure on the left axis represents the IDR fractions. The black line with dots represents the protein coverage found in Table 2. The measure on the right axis represents the protein coverage. The dashed line represents the IDR ratio of the human proteome. Can: Cancers; Car: Cardiovascular diseases; Dme: Congenital disorders of metabolism; Mal: Congenital malformations; Dig: Digestive system diseases; End: Endocrine and metabolic diseases; Imm: Immune system diseases; Mus: Musculoskeletal diseases; Ner: Nervous system diseases; Oco: Other congenital disorders; Rep: Reproductive system diseases; Res: Respiratory diseases; Ski: Skin diseases; Uri: Urinary system diseases; Oth: Other diseases.

Figure 3

Examples of proteins with pProS. The black line in the middle represents the amino acid chain, and the IDR predictions are presented below. Pink, orange, and red represent the results by MobiDB-lite, DISOPRED3, and DICHOT, respectively. The green bars represent pProSs, and the annotations defining pProS are shown above with the residue numbers of the annotations. The gray bar in the example of survival of motor neuron (SMN) represents the regions of a pseudo-pProS, which was not taken as pProS because the region of the annotation is longer than 30. In the case of low-density lipoprotein receptor adaptor protein 1 (ARH) and desmin, MobiDB-lite does not predict any IDRs. The scale of eIF4G1 (eukaryotic translation initiation factor 4 gamma 1) differs from other three.

Figure 4

Subcellular localizations by disease category. The bars represent the degree of over-representation in each of the location categories, where green represents pProS-containing proteins, and yellow represents non-pProS proteins (see also Materials and Methods). N: Nuclear; C: Cytoplasm; M: Membrane; CN: Cytoplasm and nuclear; Can: Cancers; Car: Cardiovascular diseases; Dme: Congenital disorders of metabolism; Mal: Congenital malformations; Dig: Digestive system diseases; End: Endocrine and metabolic diseases; Imm: Immune system diseases; Mus: Musculoskeletal diseases; Ner: Nervous system diseases; Oco: Other congenital disorders; Rep: Reproductive system diseases; Ski: Skin diseases; Uri: Urinary system diseases; Oth: Other diseases; All: All disease-related proteins.

Figure 5

The correlation between the number of protein–protein interactions and the number of diseases involved. The horizontal axis represents the number of diseases, and the vertical one represents the number of interactors. A box and a pair of whiskers represent quartiles, and the line in the middle of the box represents the median. The dots represent outliers.