The Role of Intrinsically Unstructured Proteins in Neurodegenerative Diseases

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2009 May 15

PMID 19440375

Citations 27

Authors

Swasti Raychaudhuri

Sucharita Dey

Nitai P Bhattacharyya

Debashis Mukhopadhyay

Affiliations

Soon will be listed here.

Abstract

The number and importance of intrinsically disordered proteins (IUP), known to be involved in various human disorders, are growing rapidly. To test for the generalized implications of intrinsic disorders in proteins involved in Neurodegenerative diseases, disorder prediction tools have been applied to three datasets comprising of proteins involved in Huntington Disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD). Results show, in general, proteins in disease datasets possess significantly enhanced intrinsic unstructuredness. Most of these disordered proteins in the disease datasets are found to be involved in neuronal activities, signal transduction, apoptosis, intracellular traffic, cell differentiation etc. Also these proteins are found to have more number of interactors and hence as the proportion of disorderedness (i.e., the length of the unfolded stretch) increased, the size of the interaction network simultaneously increased. All these observations reflect that, "Moonlighting" i.e. the contextual acquisition of different structural conformations (transient), eventually may allow these disordered proteins to act as network "hubs" and thus they may have crucial influences in the pathogenecity of neurodegenerative diseases.

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References

Uversky V, Oldfield C, Dunker A . Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys. 2008; 37:215-46. DOI: 10.1146/annurev.biophys.37.032807.125924. View

Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U . A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Mol Cell. 2004; 15(6):853-65. DOI: 10.1016/j.molcel.2004.09.016. View

Skrabana R, Sevcik J, Novak M . Intrinsically disordered proteins in the neurodegenerative processes: formation of tau protein paired helical filaments and their analysis. Cell Mol Neurobiol. 2006; 26(7-8):1085-97. PMC: 11731881. DOI: 10.1007/s10571-006-9083-3. View

Raychaudhuri S, Majumder P, Sarkar S, Giri K, Mukhopadhyay D, Bhattacharyya N . Huntingtin interacting protein HYPK is intrinsically unstructured. Proteins. 2007; 71(4):1686-98. DOI: 10.1002/prot.21856. View

Davies S, Turmaine M, Cozens B, DiFiglia M, Sharp A, Ross C . Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997; 90(3):537-48. DOI: 10.1016/s0092-8674(00)80513-9. View

Iakoucheva L, Brown C, Lawson J, Obradovic Z, Dunker A . Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol. 2002; 323(3):573-84. DOI: 10.1016/s0022-2836(02)00969-5. View

Tompa P, Szasz C, Buday L . Structural disorder throws new light on moonlighting. Trends Biochem Sci. 2005; 30(9):484-9. DOI: 10.1016/j.tibs.2005.07.008. View

Jonsson P, Bates P . Global topological features of cancer proteins in the human interactome. Bioinformatics. 2006; 22(18):2291-7. PMC: 1865486. DOI: 10.1093/bioinformatics/btl390. View

Masino L, Kelly G, Leonard K, Trottier Y, Pastore A . Solution structure of polyglutamine tracts in GST-polyglutamine fusion proteins. FEBS Lett. 2002; 513(2-3):267-72. DOI: 10.1016/s0014-5793(02)02335-9. View

10.

Uversky V . A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders. J Biomol Struct Dyn. 2003; 21(2):211-34. DOI: 10.1080/07391102.2003.10506918. View

11.

Agorogiannis E, Agorogiannis G, Papadimitriou A, Hadjigeorgiou G . Protein misfolding in neurodegenerative diseases. Neuropathol Appl Neurobiol. 2004; 30(3):215-24. DOI: 10.1111/j.1365-2990.2004.00558.x. View

12.

Linding R, Jensen L, Diella F, Bork P, Gibson T, Russell R . Protein disorder prediction: implications for structural proteomics. Structure. 2003; 11(11):1453-9. DOI: 10.1016/j.str.2003.10.002. View

13.

Uversky V . Amyloidogenesis of natively unfolded proteins. Curr Alzheimer Res. 2008; 5(3):260-87. PMC: 2719783. DOI: 10.2174/156720508784533312. View

14.

Baxendale S, Abdulla S, Elgar G, Buck D, Berks M, Micklem G . Comparative sequence analysis of the human and pufferfish Huntington's disease genes. Nat Genet. 1995; 10(1):67-76. DOI: 10.1038/ng0595-67. View

15.

Li , Romero , Rani , Dunker , Obradovic . Predicting Protein Disorder for N-, C-, and Internal Regions. Genome Inform Ser Workshop Genome Inform. 2000; 10:30-40. View

16.

Haynes C, Oldfield C, Ji F, Klitgord N, Cusick M, Radivojac P . Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol. 2006; 2(8):e100. PMC: 1526461. DOI: 10.1371/journal.pcbi.0020100. View

17.

Patil A, Nakamura H . Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in interaction networks. FEBS Lett. 2006; 580(8):2041-5. DOI: 10.1016/j.febslet.2006.03.003. View

18.

Xu J, Li Y . Discovering disease-genes by topological features in human protein-protein interaction network. Bioinformatics. 2006; 22(22):2800-5. DOI: 10.1093/bioinformatics/btl467. View

19.

Romero , Obradovic , Dunker . Sequence Data Analysis for Long Disordered Regions Prediction in the Calcineurin Family. Genome Inform Ser Workshop Genome Inform. 1997; 8:110-124. View

20.

Sticht H, Bayer P, Willbold D, Dames S, Hilbich C, Beyreuther K . Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease. Eur J Biochem. 1995; 233(1):293-8. DOI: 10.1111/j.1432-1033.1995.293_1.x. View