What are intrinsically disordered proteins (IDPs)? And how do they differ from ordered proteins?

Published on December 2nd, 2019

What are intrinsically disordered proteins (IDPs)

In the last decade the research surrounding intrinsically disordered proteins (IDPs) has dramatically increased. This increased attention is reflected in the rise of articles being published that discuss how attractive IDPs are as drug targets1. But, despite the knowledge we have gained, there’s still a lot of mystery surrounding IDPs. In this article we explain what IDPs are and how they differ from ordered globular proteins, both in terms of structure and their key characteristics.

Figure 1: A graph showing the number of publications covering IDPs over time. Data sourced from:

What are intrinsically disordered proteins (IDPs)?

IDPs and proteins with intrinsically disordered protein regions (IDPRs) make up around 30% of the human proteome. The key characteristic of IDPs and IDPRs is that they are unable to fold spontaneously into single, well-defined 3D structures, but instead fluctuate between multiple conformations. IDPs cannot be characterized by the traditional methods of structural biology very easily and so new technologies to investigate their structure and behavior are being sought after.

The classical structure-function paradigm where two proteins (with highly structured states determined by their respective amino acid sequences) bind together via a “lock and key” model has been taught for more than a century. However, many proteins have been discovered that do not require a unique structure to carry out their function2. These types of proteins, that carry structure independent functions, are classified as IDPs. There are also proteins that exist which contain both ordered domains and intrinsically disordered protein regions (IDRs). One example is p53, which has IDRs in its N- and C-terminus. These IDRs have binding sites for many partner proteins.

Figure 2: A comparison of the key characteristics between structured ordered domains versus intrinsically disordered regions. The inclusion of disordered regions and structured domains is shown to increase the versatility of proteins in eukaryota. Source: Babu et al. 20123.

How prevalent are IDPs?

IDPs an IDPRs have now been found throughout nature in proteomes of organisms in all kingdoms of life4. Interestingly, it has now been shown through various computational analyses, that the abundance of disorder increases proportionally with organism complexity4,5. It is through these computational analyses that the (presumed) number of sequences with predicted IDPRs (>30 residues) is roughly the same in bacteria/archaea, but is significantly higher in eukaryota6,7. This increase is estimated to be due to the higher number of cell signaling pathways that rely on IDPs/IDPRs.

Almost immediately after the biological world began to recognize IDPs/IDPRs as a new class of biologically active proteins, it became clear that they were not rare exceptions but highly prevalent in nature. The first collection of IDPRs included 67 disordered regions found in 61 PDB proteins8. At present, researchers have shown that there are now approximately 1,150 proteins in the list of validated IDPs9. Similarly, the Swiss Protein Database showed that long IDPRs of at least 40 consecutive residues are predicted to be in over 15,000 proteins10.

The characteristics of IDPs that inform their structure and function

IDPs do not follow the rules established by ordered globular proteins and domains. These structural differences appear to be rooted in the peculiarities of the amino acid sequences in IDPs. So called “order promoting residues” such as Tryptophan, Cysteine, Tyrosine and Leucine are depleted in IDPs. On the other hand, “disorder promoting residues” such as Arginine, Proline, Glycine and Serine are found to be relatively higher in IDPs compared to ordered proteins11.

Just as with ordered proteins, whose biological structures are formed based on their amino acid sequences, the ability of IDPs to not fold and still be functional in the absence of unique structures is also encoded into the amino acid sequences of IDPs/IDPRs. In extended IDPs, these features include multiple charged groups (typically negative) that give the IDP its characteristic high net charge at neutral pH and their extreme isoelectric values12-14. It is these features that allow IDP/IDPRs to continue to function in conditions that ordered proteins would find too harsh such as environments with high pH.

These characteristics above, coupled with their low number of hydrophobic amino acid residues13, allow for IDPs to be dis/ordered at one moment in time, but able to change state at a future point in time. Therefore, IDPs are not homogeneous, but represent a very complex mixture of partially foldable, potentially foldable, differently foldable, or completely unfoldable segments15.


In this article we have covered what IDP/IDPRs are and how they differ from ordered proteins in both their structure and their characteristics. There is still lots of mystery surrounding IDP/IDPRs given that they contradict the basic logic of the “lock-and-key” theory of protein functionality and that they break multiple rules devised by the researchers studying structure, folding, and functions of ordered proteins. An accurate understanding of multilevel complexity of IDPs/IDPRs will require the development of new rules and new technologies to study them.


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