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The role of intrinsically unstructured proteins in neurodegenerative diseases - PubMed

The role of intrinsically unstructured proteins in neurodegenerative diseases

Swasti Raychaudhuri et al. PLoS One. 2009.

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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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Intrinsically unstructured proteins are prevalent in neurodegenerative disease dataset.

A: Considering all the 352 members of the disease datasets, about 80% of the proteins were found to be unstructured compared to 73.4% and 47.7% in “control datasets 1 and 2” respectively. Level of significance was calculated by Z-test and the Z-values indicate that unstructuredness is highly prevalent in the disease dataset compared to “control datasets 1 and 2” (denoted by * and #). B: The percentage of proteins in HD, PD and AD datasets with ≥40 to ≥100 consecutive residues unstructured compared to “control datasets 1 and 2”. Levels of significance was calculated by Z-test throughout indicating significant prevalence of proteins having ≥40 to ≥100 consecutive residues unstructured in the HD datasets compared to “control dataset 1” and denoted by $ in each cases. In PD and AD dataset no such significant prevalence was observed. However, compared to “control dataset 2” proteins having ≥40 to ≥100 consecutive residues unstructured are significantly enriched in HD, PD and AD datasets and denoted by #. C, D & E: Unstructuredness is significantly prevalent in the “hub” proteins involved in neurodegenerative diseases. All the proteins in HD, PD and AD datasets were analyzed for the presence of “hub” and “end” proteins and the percentage of IUPs among the “hub” and “end” proteins in the disease datasets were calculated and plotted. Irrespective of the definition of “hub” (protein with ≥10 interactors (C), protein with ≥5 interactors (D) or protein with ≥20 interactors (E), IUPs were significantly prevalent among “hub” proteins. Levels of significance were calculated by Student's t-test and P values were 0.014 (C), 0.011 (D) and 0.012 (E) respectively, indicated by * in each panel.

Figure 2
Figure 2. Functional annotations of the proteins in disease datasets.

All the protein IDs for HD, PD and AD datasets were submitted separately in batch to annotate the biological process by the “PANTHER biological process” annotation tool and the results were tabulated and analyzed. Biological processes that were significantly enriched with proteins in HD, PD and AD protein datasets compared to total human proteome dataset are indicated in figure by # (for HD), * (for PD) and $ (for AD). Level of significance in each case was calculated by Chi-square test. Chi-square test was performed and p values were calculated with the aid of “GraphPad QuickCalcs” (

http://www.graphpad.com/quickcalcs/chisquared1.cfm

).

Figure 3
Figure 3. Prevalence of unstructuredness in biological processes enriched with proteins from HD, PD and AD datasets.

A: Except for carbohydrate metabolism and electron transport, proteins involved in all other important biological processes, as indicated, are significantly enriched in unstructured proteins in HD. Levels of significance were calculated by Z-test indicating confidence level of 95% in each case. B: Proteins involved in all the important processes in PD as shown in figure are significantly enriched in unstructured proteins. Levels of significance were calculated by Z-test indicating confidence level of 95% in each case. C: Except processes like coenzyme and prosthetic group metabolism and immunity and defense, proteins involved in all other important processes in AD, as mentioned, are significantly enriched in unstructured proteins.

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References

    1. Tompa P, Szász C, Buday L. Structural disorder throws new light on moonlighting. Trends Biochem Sci. 2005;30:484–489. - PubMed
    1. Tompa P, Fuxreiter M. Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci. 2008;33:2–8. - PubMed
    1. Tompa P. Intrinsically Unstructured Proteins. Trends Biochem Sci. 2002;27:527–533. - PubMed
    1. Sickmeier M, Hamilton JA, LeGall T, Vacic V, Cortese MS, et al. DisProt: the Database of Disordered Proteins. Nucleic Acids Res. 2007;35:D786–793. - PMC - PubMed
    1. Dunker AK, Obradovic Z, Romero P, Garner EC, Brown CJ. Intrinsic protein disorder in complete genomes. Genome Informatics Series: Proceedings of the Workshop on Genome Informatics. 2000;11:161–171. - PubMed

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