Disordered Proteins


Intrinsically disordered proteins (IDPs) and disordered protein regions (IDPRs) do not have a specific three‐dimensional (3D) structure in their unbound states under physiological conditions, existing instead as dynamic structural ensembles. There are also subtler categories of disorder, such as conditional (or dormant) disorder and partial disorder. Both the ability of a protein/region to fold and the predisposition to stay intrinsically disordered are encoded in the amino acid sequence. Structurally, IDPs/IDPRs are characterised by high spatiotemporal heterogeneity. It is important to remember, however, that although structure and disorder are often treated as binary states, they actually sit on a structural continuum. Functionally, IDPs/IDPRs are often characterised by the ability to multitask and be promiscuous binders. The field of unstructural biology has arisen to explain proteins that fall outside of the classical structure–function paradigm. A major goal in the coming years will be to understand sequence‐to‐function relationships for disordered proteins.

Key Concepts

  • Many biologically important protein regions fail to form specific three‐dimensional (3D) structures in their unbound states under physiological conditions.
  • Amino acid sequences of these intrinsically disordered proteins (IDPs) are noticeably different from sequences of ordered proteins and reliable predictors can be developed to distinguish the tendency of a protein to be structured or disordered.
  • IDPs are highly abundant in nature and have numerous functions that complement the functional repertoire of ordered proteins.
  • IDPs are characterised by high structural heterogeneity, and there is a structural continuum, with highly ordered proteins on one end and highly disordered proteins on the other.
  • IDPs/IDPRs are commonly found in various human diseases where they often play crucial roles in pathogenesis.
  • IDPs are crucial constituents of various membraneless organelles abundantly found in the cytoplasm and nucleoplasm of eukaryotic cells.

Keywords: unfolded; flexible; unstructured; protein function; structural heterogeneity; binding promiscuity; multifunctionality

Figure 1. Amino acid scales and disorder and order promoting residues. Top: Ranking of the 20 amino acids by the Kyte–Doolittle hydrophobicity scale from the most to the least hydrophobic. Bottom: Ranking of the amino acids from the most to the least flexible by Vihinen's flexibility scale.
Figure 2. Correlation between the intrinsic disorder content and proteome size for 3484 species from viruses, archaea, bacteria and eukaryotes. Each symbol indicates a species. There are totally six groups of species: viruses expressing one polyprotein precursor (small red circles filled with blue), other viruses (small red circles), bacteria (small green circles), archaea (blue circles), unicellular eukaryotes (brown squares) and multicellular eukaryotes (pink triangles). Each viral polyprotein was analysed as a single polypeptide chain, without parsing it into the individual proteins before predictions. The proteome size is the number of proteins in the proteome of that species and is shown in log base. The average fraction of disordered residues is calculated by averaging the fraction of disordered residues of each sequence over all the sequences of that species. Disorder prediction is evaluated by PONDR‐VSL2B. Generated based on the results published in Xue et al. .
Figure 3. Structural heterogeneity of IDPs (intrinsically disordered proteins)/IDPRs (intrinsically disordered protein regions). Top half: Bicoloured view of functional proteins that are considered to be either ordered (folded, blue) or completely structureless (disordered, red). Ordered proteins are taken as rigid rocks, whereas IDPs are considered as completely structureless entities, similarly to cooked noodles. Bottom half: A continuous emission spectrum representing the fact that functional proteins can extend from fully ordered to completely structureless proteins, with everything in between. Intrinsic disorder can have multiple faces, can affect different levels of protein structural organisation and whole proteins, or various protein regions, can be disordered to a different degree. Some illustrative examples include ordered proteins that are completely devoid of disordered regions (rock‐like type), ordered proteins with limited number of disordered regions (grass‐on‐the rock type), ordered proteins with significant amount of disordered regions (llama/camel hair type), molten globule‐like collapsed IDPs (greasy ball type), premolten globule‐like extended IDPs (spaghetti‐and‐sausage type) and unstructured extended IDPs (hairball type). Reproduced with permission from Uversky©John Wiley and Sons.
Figure 4. Peculiarities of one‐to‐many (a and b) and many‐to‐one interactions (c and d) based on intrinsic disorder. (a) Primary, secondary and quaternary structure of the four overlapping complexes in the C‐terminus of p53. (b) The ΔASA for rigid association between the components of complexes for each residue in the relevant sequence region of p53. (c) Sequence alignment of five peptides bound to 14‐3‐3ξ and the RMSF of their conformations. (d) Aligned ribbon representations of the structures of the five peptides, which were aligned through multiple alignment of their respectively bound 14‐3‐3 domains, shown along with a representative ribbon representation of a 14‐3‐3 domain. Reproduced from Oldfield et al. © Science+Business Media under the Creative Commons Attribution 2.0 (CC BY) license.


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DeForte, Shelly, and Uversky, Vladimir N(Sep 2016) Disordered Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020213.pub2]