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. 2022 Nov 19;14(6):1487–1493. doi: 10.1007/s12551-022-01016-7

Enrichment patterns of intrinsic disorder in proteins

Ashwini Patil 1,✉
PMCID: PMC9842814  PMID: 36659984

Abstract

Intrinsically disordered regions in proteins have been shown to be important in protein function. However, not all proteins contain the same amount of intrinsic disorder. The variation in the levels of intrinsic disorder in different types of proteins has been extensively studied over the last two decades. It is now known that the levels of intrinsic disorder vary in proteins across organisms, functions, diseases, and cellular locations. This review consolidates the known trends in the abundance of intrinsic disorder identified in groups of proteins across varying conditions and functions. It also presents new data towards the understanding of intrinsic disorder in cell type-specific proteins.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12551-022-01016-7.

Keywords: Intrinsic disorder, Cell type-specific proteins, Protein

Introduction

The three-dimensional structure of a protein plays an important role in the way it functions in the cell. Proteins are broadly classified into two categories based on their structure: globular proteins and intrinsically unstructured proteins (Wright and Dyson 1999). Globular proteins, or those with a fixed three-dimensional structure, largely maintain this structure under physiological conditions. They may show some local flexibility in the form of small loops and coils, but are predominantly structured, and their function depends on their structure. On the other hand, intrinsically unstructured proteins, or intrinsically disordered proteins (IDPs), are flexible due to the presence of large intrinsically disordered regions (IDRs) which can take on an ensemble of conformations under physiological conditions (Uversky et al. 2000). IDPs can either be completely disordered or contain a combination of large unstructured regions along with several globular domains.

The prevalence of intrinsic disorder in proteins has been widely studied for the past two decades. While IDRs are common in organisms (Ward et al. 2004), their abundance is not uniform in proteins. In fact, IDRs are known to be present in varying abundances across different groups of proteins based their ability to interact, their function, their cellular location, and the organism in which they are present. This review looks at the trends of abundance of IDRs in proteins across various conditions in order to provide a better understanding of intrinsic disorder and its role protein function (Fig. 1).

Fig. 1.

Fig. 1

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Overview of groups of proteins based on characteristics and functionality that have been found to be enriched in intrinsically disordered regions

Intrinsic disorder in proteins and interaction networks

Interactions of proteins in organisms are important in function. As such, the role of intrinsic disorder in protein–protein interactions has been extensively studied (Uversky 2015; Mollica et al. 2016; Arai 2018; Yang et al. 2019). The proteins in an interaction network are divided into two types based on the number of interaction partners they have (i) hubs which interact with a large number of interaction partners (definitions vary, but usually a protein with more than 5 interactions is considered a hub) and (ii) non-hubs which interact with only one or a few partner proteins. Intrinsic disorder has been identified in greater levels in hub proteins compared to non-hub proteins (Dunker et al. 2005; Patil and Nakamura 2006). Hub proteins have been further classified into subtypes such as obligate and transient. Obligate hubs participate in interactions within protein complexes, while transient hubs interact with multiple partner proteins for a short duration. Though these definitions still continue to be fluid, it has been observed that transient hubs have greater disorder than obligate hubs (Singh et al. 2007). IDRs are also enriched in protein-binding globular hubs (Kim et al. 2008; Bugge et al. 2021).

The structural flexibility provided by IDRs in proteins allows them to adopt multiple conformations facilitating binding to various partner proteins, thus resulting in their central role in protein–protein interaction networks (Hu et al. 2017). These IDRs may either be in the form of linkers between globular domains, or as part of disordered domains containing large unstructured regions. It has been shown that the amount of intrinsic disorder in hubs decreases as the number of ordered protein domains increases (Patil et al. 2010). Proteins with IDRs can bind to their interaction partners either directly using the disordered region or using globular domains that are separated by IDRs. IDPs interact with other proteins and ligands either by folding upon binding, staying partially unstructured after binding to form fuzzy complexes, or staying completely unstructured even in the bound state (Borgia et al. 2018). IDRs use several features to bind specific partner proteins (Cumberworth et al. 2013). Molecular recognition features (MoRFs) are short, flexible regions of 10–70 residues that are present within IDRs (Mohan et al. 2006). They have the ability to undergo a disorder-to-order transition allowing them to bind multiple proteins. Another means of binding in IDRs are small linear motifs. These are enriched within IDRs and have been shown to provide binding sites to partner proteins (Davey et al. 2017).

In addition to structural flexibility, alternative splicing events (Romero et al. 2006) and post-translational modifications (Iakoucheva et al. 2002) also increase the binding repertoire of proteins with IDRs (Hsu et al. 2013). The presence of multiple binding sites, or multivalency, in IDPs also helps their ability to bind multiple ligands (Fung et al. 2018). Additionally, flanking regions and the context of the interaction play an important role in the binding affinity and specificity of IDPs (Bugge et al. 2020). Proteins that use globular domains separated by IDRs to bind interaction partners use the flexibility of the interspersed disordered regions to position the globular domains in various orientations, thus allowing an extended binding repertoire. The binding of IDPs greatly depends on their ability to reduce the entropic cost of moving from structural flexibility in the unbound state to increasing conformational rigidity when bound to another protein (Mittag et al. 2010). Short linear motifs, multiple binding sites interspersed with flexible regions, and binding regions that remain partially unstructured, along with post-translational modifications and alternating splicing events in IDPs, all help reduce this entropic cost and increase enthalpic gain facilitating binding (Flock et al. 2014).

Intrinsic disorder in protein function and disease

The prevalence of IDRs has been found to vary in proteins from different functional categories. IDRs are especially abundant in proteins involved in cell signaling and regulatory processes (Berlow et al. 2015; Wright and Dyson 2015), contributing extensively at every step in all categories of signaling pathways across all kingdoms of life (Bondos et al. 2022). Post-translational modifications play a large role in the functional modulation of IDPs (Bah and Forman-Kay 2016). As such, the amounts of IDPs are tightly regulated within the cell through rapid turnover times and greater levels of alternative splicing and post-translational modifications (Gsponer et al. 2008). The chemical composition of sequences of IDRs has been shown to have an effect on their function, and is thus conserved, despite poor sequence conservation (Moesa et al. 2012). For instance, positively charged IDRs are enriched in RNA processing and chromatin modification, while polar IDRs are enriched in signal transduction The length and composition of a disordered region also affect the degradation of the protein (Fishbain et al. 2015).

Along with their role in cell signaling, IDRs have also been found to function in proteins helping organisms survive under environmental stress (French-Pacheco et al. 2022), in desiccation tolerance (Janis et al. 2018) and in the circadian circuit (Pelham et al. 2020). They have been identified in transmembrane proteins (Kjaergaard and Kragelund 2017), keratinocytes (Shamilov et al. 2021), and RNA- and DNA-binding proteins (Salladini et al. 2020; Musselman and Kutateladze 2021; Zhao et al. 2021a; Brodsky et al. 2021). Given their important role in cellular function, it follows that missense mutations in IDRs can result in disease despite showing weaker evolutionary conservation than ordered domains (Brown et al. 2011; Ahmed et al. 2022). Mutations in IDRs can result in short linear motifs causing unwanted binding events leading to diseases (Meyer et al. 2018). IDRs have been found in proteins implicated in various diseases including cancer (Iakoucheva et al. 2002; Anbo et al. 2019). IDRs can also form pathogenic aggregates resulting in neurogenerative diseases (Candelise et al. 2021).

Intrinsic disorder in organism complexity and cellular location

The complexity of an organism is measured as the number of distinct cell types present in it. Various studies have looked at the role of intrinsic disorder in organism complexity. Tompa et al. observed increased protein disorder content in more complex organisms, with greater levels of intrinsic disorder in eukaryotes compared to prokaryotes (Tompa et al. 2006). Schad et al. studied intrinsic disorder in proteins in relation to organism complexity as seen in prokaryotes and non-plant eukaryotes (Schad et al. 2011). However, they found no correlation between the amount of intrinsic disorder present in the organism proteome and its complexity in eukaryotes. They also did not find any correlation between the level of disorder and the proteome size. A more detailed study analyzing the amount of intrinsic disorder in proteins across viruses, archea, bacteria, and eukaryotes confirmed these findings (Xue et al. 2010, 2012). Xue et al. also discovered that the habitat of an organism affects the levels of intrinsic disorder in its proteins. For instance, halophiles and methanophiles show increased disorder compared to thermophiles (Xue et al. 2010). The largest variance in the levels of intrinsic disorder was observed in viruses, whereas the smallest was observed in multicellular eukaryotes, and no significant difference was found between the levels of intrinsic disorder in unicellular and multicellular eukaryotes. The highest amount of intrinsic disorder was found in vertebrates (Vinogradov and Anatskaya 2021). Recently, a significant positive correlation has been shown between the number of protein domains that are intrinsically disordered and organismal complexity (Gao et al. 2021).

The role of intrinsic disorder in organism complexity has further led to IDRs being implicated in cell type specification since the fraction of IDRs in a proteome increases with the number of cell types (Niklas et al. 2018). IDRs have been found in protein segments containing binding motifs that are spliced in a tissue-specific manner (Buljan et al. 2012). IDPs are also specific to certain cellular compartments such as the nucleus and cytoplasm (Zhao et al. 2021b) and drive the formation of membraneless organelles (Brocca et al. 2020).

Intrinsic disorder in cell type specificity

An area that is still unexplored is the relative abundance of intrinsic disorder in cell type-specific proteins. A preliminary investigation of the prevalence of IDRs in cell type-specific proteins shows that there are indeed variations in the amount of intrinsic disorder present. For this analysis, human cell types and proteins identified in them were taken from the Human Protein Atlas (Uhlén et al. 2015), IDRs predicted in human proteins were taken from the MobiDB database (Piovesan et al. 2021), and the number of interactions of proteins were taken from the HitPredict database (30Aug2021 version) (López et al. 2015). Separating proteins into bins of increasing number of cell types in which they are present, the fraction of long IDRs (30 residues or more) was compared across bins. Supplementary Table S1 gives the full list of proteins and their features used in this analysis along with the cell type bin they were assigned to. On average, proteins present in a large number of cell types have a greater fraction of long IDRs compared to proteins present in fewer cell types (Fig. 2A, Supplementary Table S2a). Further, proteins that are commonly present in a large number of cell types have a greater number of interactions compared to cell type-specific proteins (Fig. 2B, Supplementary Table S2b).

Fig. 2.

Fig. 2

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Relationship between cell type specificity of proteins and their intrinsic disorder and interactions. A Box plot of the distribution of fraction of long disordered regions of 30 residues or more in proteins present in the specified number of cell types (Kruskal–Wallis rank sum test p value <  < 0.001). B Box plot of the distribution of log-transformed interaction counts for proteins present in the specified number of cell types (Kruskal–Wallis rank sum test p value <  < 0.001). Proteins were divided into 6 bins ranging from 0 to 60 cell types based on their presence in those cell types

Figure 3 shows some examples of proteins that are present either ubiquitously or in specific cell types and have varying levels of intrinsic disorder. Experimentally identified structures were obtained from the Protein Data Bank (Burley et al. 2021) and superimposed with structures predicted by AlphaFold (Jumper et al. 2021; Varadi et al. 2022) to indicate the location of IDRs. RLBP1 (retinaldehyde-binding protein 1) is a soluble retinoid carrier that is found in 3 cell types in the retina, participates in only 3 interactions, and does not contain any long, disordered regions (Fig. 3A). On the other hand, the E3 ubiquitin-protein ligase ZFP91 is found in 42 cell types, participates in 53 interactions, and contains one long IDR along with several smaller ones (Fig. 3B).

Fig. 3.

Fig. 3

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Examples of structures of human proteins to study the relationship between cell type specificity and intrinsic disorder. X-ray crystal or NMR structures of proteins were taken from the Protein Data Bank (orange) and superimposed with models generated by AlphaFold (blue) to indicate locations of intrinsically disordered regions. A X-ray crystal structure (4CJ6) of RLBP1, a protein found in a few cell types and having low levels of intrinsic disorder. B 5 models selected from the NMR structure (2M9A) of ZFP91, a protein found in a large number of cell types and having high levels of intrinsic disorder. C 5 models selected from the NMR structure (2FY1) of RBMY1A1, a protein found in a few cell types but having high levels of intrinsic disorder. D X-ray crystal structure (3GB8) of XPO1, a protein found in a large number of cell types but having low levels of intrinsic disorder

Further study is necessary to reconcile these results with the presence of some proteins showing apparently contradictory patterns. For instance, the RNA-binding protein RBMY1A1 is found in 4 cell types in the testis but has 2 long disordered regions and participates in 30 interactions (Fig. 3C). Despite the low median values of fractions of long IDRs in proteins present in fewer cell types (bins 0–10, 11–20, 21–30), approximately 7% of proteins in these groups show high levels of intrinsic disorder. It is possible that some of these proteins are present in more cell types than is currently documented in the Human Protein Atlas. A gene ontology enrichment analysis indicates that these proteins are abundant in repeat regions and participate in nucleic acid binding (Sherman et al. 2022). Thus, another possibility is that their level of intrinsic disorder is related to the nature of their function or the presence of repeat regions. At the other end of the spectrum are proteins like XPO1 (Exportin 1) which are found in a large number of cell types but contain no long IDRs. XPO1 is a protein with little predicted intrinsic disorder that mediates nuclear export of proteins in the cell. It is found in 45 cell types and is known to participate in well over 1200 interactions (Fig. 3D). It is possible that proteins like XPO1 contain a large number of loops or small flexible regions that allow them to participate in multiple interactions and hence function in multiple cell types. Finally, there is also the possibility that the number of interactions of a protein is the significant characteristic related to its cell type specificity and the level of intrinsic disorder is simply a consequence of that.

Future directions

It is clear that the enrichment of intrinsic disorder in proteins varies with function, location, and role in the cell. Several groups of proteins that have relatively high levels of intrinsic disorder have already been identified. A preliminary analysis shows that a relationship exists between the presence of large IDRs in proteins, the number of interactions they participate in, and the number of cell types they are found in. However, a more detailed study of these findings in human and other species is needed to provide a greater understanding of this relationship and its effect on protein function.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 1514 KB) (1.5MB, xlsx)

Declarations

Ethical approval

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Conflict of interest

AP is founder and CEO of Combinatics Inc., Japan.

Footnotes

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