Protein Disorder and Human Genetic Disease

Abstract

Intrinsically disordered proteins (IDPs) are biologically active proteins that lack stable structure under physiological conditions. They are involved in crucial biological functions related to regulation, recognition, signalling and control of various events in the cell. Misbehaviour of IDPs is commonly associated with various human diseases. IDPs represent a prominent part of the human diseasome, a network that links the human disease phenome (which includes all the human genetic diseases) with the human disease genome (which contains all the disease‐related genes), where they could be grouped into a unique entity, the human‐genetic‐disease‐associated unfoldome. The exonic single nucleotide variations (SNVs) may induce a significant change in the tendency of a protein region to be structured or disordered, thereby causing malfunction of such a protein and contributing to the disease risk. Therefore, IDPs are abundant in genetic diseases, play crucial roles in pathogenesis of these maladies, and clearly require special attention.

Key Concepts:

  • Intrinsically disordered proteins (IDPs) are common in various proteomes, where they constitute functionally broad and densely populated unfoldomes.

  • IDPs have crucial biological functions and are responsible for regulation, recognition, signalling and control of various events in the cell.

  • Dysfunction, dysregulation and misbehaviour of IDPs are related to the pathogenesis of various diseases.

  • Mutations in IDPs are frequently associated with genetic diseases.

  • Mutations affecting the potential post‐translational modification sites (which are frequently located within the intrinsically disordered regions) are often related to various diseases.

  • A more‐detailed understanding of the roles of intrinsically disordered proteins in genetic diseases might provide a basis for rational drug design against them.

Keywords: intrinsic disorder; intrinsically disordered protein; diseasome; unfoldome; genetic disease; protein–protein interaction networks; pre‐molten globule; random coil; entropic chain

Figure 1.

Abundance of intrinsic disorder in disease‐associated proteins. Percentages of disease associated proteins with ≥30 to ≥100 consecutive residues predicted to be disordered. The error bars represent 95% confidence intervals and were calculated using 1000 bootstrap re‐sampling. Corresponding data for signalling and ordered proteins are shown for the comparison. Analysed sets of disease‐related proteins included 1786, 487, 689 and 285 proteins for cancer, CVD, neurodegenerative disease and diabetes, respectively. Reproduced with permission from Uversky et al..

Figure 2.

Schematic diagram of the potential impact of the disease mutations in ordered and disordered regions. The conventional structure‐centric view of missense mutations is challenged. Disease‐associated mutations located in the intrinsically disordered protein regions are more prevalent and have a larger functional impact than previously thought. Reproduced with permission from Vacic and Iakoucheva , http://dx.doi.org/10.1039/C1MB05251A and The Royal Society of Chemistry.

Figure 3.

Disorder predictions for PYD domains of NLRP proteins: (a) NLRP10, NLRP14 and NLRP R55E mutant; (b) ASC, ASC2, NLRP3, NLRP5, NLRP7 and NLRP12; and (c) NLRP2, NLRP4, NLRP8, NLRP9, NLRP11 and NLRP13. Regions discussed in the text for each group of proteins are shown as red horizontal bars.

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Further Reading

Creamer TP (ed.) (2008) Unfolded Proteins: From Denatured to Intrinsically Disordered. In series “Scientific Revolutions” (Uversky V.N. series ed.). Hauppauge, New York, USA: Nova Science Publishers, Inc. (ISBN 978‐1‐60456‐107‐4).

Fuxreiter M and Tompa P (eds) (2011) Fuzziness: Structural Disorder in Protein Complexes. Austin, TX: Landes Biosiences Springer.

Schweitzer‐Stenner R (ed.) (in press) Folding, Misfolding and Nonfolding of Peptides and Small Proteins. In The Wiley Series in Protein and Peptide Science (Uversky V.N. series ed.). Hoboken, New Jersey, USA: John Wiley & Sons, Inc.

Tompa P (2009) Structure and Function of Intrinsically Disordered Proteins. Boca Raton: CRC Press.

Uversky VN and Longhi S (eds) (2010) Instrumental Analysis of Intrinsically Disordered Proteins: Assessing Structure and Conformation. In The Wiley Series in Protein and Peptide Science (Uversky V.N. series ed.). Hoboken, New Jersey, USA: John Wiley & Sons, Inc. (ISBN: 978‐0‐470‐34341‐8).

Uversky VN and Longhi S (eds) (in press) Flexible Viruses: Structural Disorder in Viral Proteins. In The Wiley Series in Protein and Peptide Science (Uversky V.N. series ed.). Hoboken, New Jersey, USA: John Wiley & Sons, Inc. (ISBN: 978‐0‐470‐61831‐8).

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Uversky, Vladimir N, Iakoucheva, Lilia M, and Dunker, A Keith(Feb 2012) Protein Disorder and Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023589]