Disordered Proteins

Abstract

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 .
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.2008 © Science+Business Media under the Creative Commons Attribution 2.0 (CC BY) license.
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References

Armstrong CM and Bezanilla F (1977) Inactivation of the sodium channel II. Gating current experiments. Journal of General Physiology 70: 567–590.

Brangwynne CP (2013) Phase transitions and size scaling of membrane‐less organelles. Journal of Cell Biology 203: 875–881.

Brown HG and Hoh JH (1997) Entropic exclusion by neurofilament sidearms: a mechanism for maintaining interfilament spacing. Biochemistry 36: 15035–15040.

Buljan M, Chalancon G, Eustermann S, et al. (2012) Tissue‐specific splicing of disordered segments that embed binding motifs rewires protein interaction networks. Molecular Cell 46: 871–883.

Bustos DM and Iglesias AA (2006) Intrinsic disorder is a key characteristic in partners that bind 14‐3‐3 proteins. Proteins: Structure, Function, and Bioinformatics 63: 35–42.

Dunker AK, Lawson JD, Brown CJ, et al. (2001) Intrinsically disordered protein. Journal of Molecular Graphics and Modelling 19: 26–59.

Dunker AK, Brown CJ and Obradovic Z (2002) Identification and functions of usefully disordered proteins. Advances in Protein Chemistry 62: 25–49.

Dunker AK, Cortese MS, Romero P, Iakoucheva LM and Uversky VN (2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS Journal 272: 5129–5148.

Dyson HJ and Wright PE (2005) Intrinsically unstructured proteins and their functions. Nature Reviews. Molecular Cell Biology 6: 197–208.

Erkut C, Vasilj A, Boland S, et al. (2013) Molecular strategies of the Caenorhabditis elegans dauer larva to survive extreme desiccation. PLoS One 8: e82473.

Gsponer J, Futschik ME, Teichmann SA and Babu MM (2008) Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Science 322: 1365–1368.

van der Gucht J, Spruijt E, Lemmers M and Cohen Stuart MA (2011) Polyelectrolyte complexes: bulk phases and colloidal systems. Journal of Colloid and Interface Science 361: 407–422.

Gunasekaran K, Tsai CJ and Nussinov R (2004) Analysis of ordered and disordered protein complexes reveals structural features discriminating between stable and unstable monomers. Journal of Molecular Biology 341: 1327–1341.

He B, Wang K, Liu Y‐L, et al. (2009) Predicting intrinsic disorder in proteins: an overview. Cell Research 19: 929–949.

Hendus‐Altenburger R, Pedraz‐Cuesta E, Schnell JA, et al. (2015) The human Na+/H+ exchanger 1 is a membrane scaffold protein for extracellular signal‐regulated kinase 2. BMC Biology 14: 31.

Hoh JH (1998) Functional protein domains from the thermally driven motion of polypeptide chains: a proposal. Proteins: Structure, Function, and Bioinformatics 32: 223–228.

Holt C and Sawyer L (1993) Caseins as rheomorphic proteins: interpretation of primary and secondary structures of the αs1‐, β‐, and k‐caseins. Journal of the Chemical Society, Faraday Transactions 89: 2683–2692.

Hoshi T, Zagotta WN and Aldrich RW (1990) Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250: 533–538.

Keating CD (2012) Aqueous phase separation as a possible route to compartmentalization of biological molecules. Accounts of Chemical Research 45: 2114–2124.

Kriwacki RW, Hengst L, Tennant L, Reed SI and Wright PE (1996) Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2‐bound state: conformational disorder mediates binding diversity. Proceedings of the National Academy of Sciences of the United States of America 93: 11504–11509.

Kovacs D, Agoston B and Tompa P (2008) Disordered plant LEA proteins as molecular chaperones. Plant Signaling & Behavior 3: 710–713.

Kyte J and Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. Journal of Molecular Biology 157: 105–132.

Malaney P, Pathak RR, Xue B, et al. (2013) Intrinsic disorder in PTEN and its interactome confers structural plasticity and functional versatility. Scientific Reports 3: 2035.

Mark WY, Liao JC, Lu Y, et al. (2005) Characterization of segments from the central region of BRCA1: an intrinsically disordered scaffold for multiple protein‐protein and protein‐DNA interactions? Journal of Molecular Biology 345: 275–287.

Mittag T, Orlicky S, Choy WY, et al. (2008) Dynamic equilibrium engagement of a polyvalent ligand with a single‐site receptor. Proceedings of the National Academy of Sciences of the United States of America 105: 17772–17777.

Nash P, Tang X, Orlicky S, et al. (2001) Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 414: 514–521.

Nott TJ, Petsalaki E, Farber P, et al. (2015) Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Molecular Cell 57: 936–947.

Oldfield CJ, Cheng Y, Cortese MS, et al. (2005) Comparing and combining predictors of mostly disordered proteins. Biochemistry 44: 1989–2000.

Oldfield CJ, Meng J, Yang JY, et al. (2008) Flexible nets: disorder and induced fit in the associations of p53 and 14‐3‐3 with their partners. BMC Genomics 9: S1.

Pederson T (2001) Protein mobility within the nucleus‐‐what are the right moves? Cell 104: 635–638.

Pejaver V, Hsu W‐L, Xin F, et al. (2014) The structural and functional signatures of proteins that undergo multiple events of post‐translational modification. Protein Science 23: 1077–1093.

Phair RD and Misteli T (2000) High mobility of proteins in the mammalian cell nucleus. Nature 404: 604–609.

Podlaha O and Zhang J (2003) Positive selection on protein‐length in the evolution of a primate sperm ion channel. Proceedings of the National Academy of Sciences of the United States of America 100: 12241–12246.

Radivojac P, Vucetic S, O'Connor TR, et al. (2006) Calmodulin signaling: analysis and prediction of a disorder‐dependent molecular recognition. Proteins: Structure, Function, and Bioinformatics 63: 398–410.

Romero PR, Zaidi S, Fang YY, et al. (2006) Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proceedings of the National Academy of Sciences of the United States of America 103: 8390–8395.

Santner AA, Croy CH, Vasanwala FH, et al. (2012) Sweeping away protein aggregation with entropic bristles: intrinsically disordered protein fusions enhance soluble expression. Biochemistry 51: 7250–7262.

Schulz GE (1979) Nucleotide binding proteins. In: Balaban M (ed.) Molecular Mechanisms of Biological Recognition, pp. 79–94. New York: Elsevier/North‐Holland Biomedical Press.

Sharma R, Raduly Z, Miskei M and Fuxreiter M (2015) Fuzzy complexes: specific binding without complete folding. FEBS Letters 589: 2533–2542.

Tompa P and Csermely P (2004) The role of structural disorder in the function of RNA and protein chaperones. FASEB Journal 18: 1169–1175.

Tompa P and Fuxreiter M (2008) Fuzzy complexes: polymorphism and structural disorder in protein‐protein interactions. Trends in Biochemical Sciences 33: 2–8.

Uversky VN, Gillespie JR and Fink AL (2000) Why are ‘natively unfolded’ proteins unstructured under physiologic conditions? Proteins: Structure, Function, and Bioinformatics 41: 415–427.

Uversky VN, Oldfield CJ and Dunker AK (2005) Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. Journal of Molecular Recognition 18: 343–384.

Uversky VN, Roman A, Oldfield CJ and Dunker AK (2006) Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs. Journal of Proteome Research 5: 1829–1842.

Uversky VN, Oldfield CJ and Dunker AK (2008) Intrinsically disordered proteins in human diseases: Introducing the D2 concept. Ann. Rev. Biophys. Biomol. Structure. 37: 215–246.

Uversky VN and Dunker AK (2010) Understanding protein non‐folding. Biochimica et Biophysica Acta ‐ Proteins and Proteomics 1804: 1231–1264.

Uversky VN (2011) Multitude of binding modes attainable by intrinsically disordered proteins: a portrait gallery of disorder‐based complexes. Chemical Society Reviews 40: 1623–1634.

Uversky VN and Dunker AK (2012) A multiparametric analysis of intrinsically disordered proteins: looking at intrinsic disorder through compound eyes. Analytical Chemistry 84: 2096–2104.

Uversky VN (2013a) Unusual biophysics of intrinsically disordered proteins. Biochimica et Biophysica Acta ‐ Proteins and Proteomics 1834: 932–951.

Uversky VN (2013b) A decade and a half of protein intrinsic disorder: biology still waits for physics. Protein Science 22: 693–724.

Uversky VN (2014) The triple power of D3: protein intrinsic disorder in degenerative diseases. Frontiers in Bioscience (Landmark Edition) 19: 181–258.

Uversky VN, Davé V, Eliezer D, et al. (2014) Pathological unfoldomics of uncontrolled chaos: intrinsically disordered proteins and human diseases. Chemical Reviews 114: 6844–6879.

Uversky VN, Kuznetsova IM, Turoverov KK and Zaslavsky B (2015) Intrinsically disordered proteins as crucial constituents of cellular aqueous two phase systems and coacervates. FEBS Letters 589: 15–22.

Vihinen M, Torkkila E and Riikonen P (1994) Accuracy of protein flexibility predictions. Proteins: Structure, Function, and Bioinformatics 19: 141–149.

Weinreb PH, Zhen W, Poon AW, Conway KA and Lansbury PT Jr (1996) NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 35: 13709–13715.

Wootton JC (1994) Non‐globular domains in protein sequences: automated segmentation using complexity measures. Computers and Chemistry 18: 269–285.

Wright PE and Dyson HJ (1999) Intrinsically unstructured proteins: re‐assessing the protein structure–function paradigm. Journal of Molecular Biology 293: 321–331.

Xue B, Dunker AK and Uversky VN (2012) Orderly order in protein intrinsic disorder distribution: disorder in 3500 proteomes from viruses and the three domains of life. Journal of Biomolecular Structure and Dynamics 30: 137–149.

Xue B, Romero PR, Noutsou M, et al. (2013) Stochastic machines as a colocalization mechanism for scaffold protein function. FEBS Letters 587: 1587–1591.

Further Reading

Fuxreiter M, Tóth‐Petróczy A, Kraut DA, et al. (2014) Disordered proteinaceous machines. Chemical Reviews 114: 6806–6843.

Habchi J, Tompa P, Longhi S and Uversky VN (2014) Introducing protein intrinsic disorder phenomenon. Chemical Reviews 114: 6561–6588.

Jacob U, Kriwacki R and Uversky VN (2014) Conditionally and transiently disordered proteins: awakening cryptic disorder to regulate protein function. Chemical Reviews 114: 6779–6805.

van der Lee R, Buljan M, Lang B, et al. (2014) Classification of intrinsically disordered proteins and regions. Chemical Reviews 114: 6589–6631.

Namba K (2001) Roles of partly unfolded conformations in macromolecular self‐assembly. Genes to Cells 6: 1–12.

Oldfield CJ and Dunker AK (2014) Intrinsically disordered proteins and intrinsically disordered protein regions. Annual Review of Biochemistry 83: 553–584.

Tompa P (2010) Structure and Function of Intrinsically Disordered Proteins, 331 pp. Boca Raton: CRC Press.

Tompa P, Schad E, Tantos A and Kalmar L (2015) Intrinsically disordered proteins: emerging interaction specialists. Current Opinion in Structural Biology 35: 49–59.

Uversky VN and Longhi S (eds) (2010) Instrumental Analysis of Intrinsically Disordered Proteins: Assessing Structure and Conformation (The Wiley Series in Protein and Peptide Science, Uversky VN series editor), 744 pp. Hoboken, New Jersey: John Wiley & Sons, Inc..

Wright PE and Dyson HJ (2015) Intrinsically disordered proteins in cellular signalling and regulation. Nature Reviews Molecular Cell Biology 16: 18–29.

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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]