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This article is part of the supplement: The 2008 International Conference on Bioinformatics & Computational Biology (BIOCOMP'08)

Open Access Research

Protein disorder in the human diseasome: unfoldomics of human genetic diseases

Uros Midic1, Christopher J Oldfield2, A Keith Dunker3, Zoran Obradovic1* and Vladimir N Uversky345*

Author Affiliations

1 Center for Information Science and Technology, Temple University, Philadelphia, PA 19122, USA

2 Center for Computational Biology and Bioinformatics, Indiana University School of Informatics, Indianapolis, IN 46202, USA

3 Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

4 Institute for Intrinsically Disordered Protein Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA

5 Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

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BMC Genomics 2009, 10(Suppl 1):S12  doi:10.1186/1471-2164-10-S1-S12

Published: 7 July 2009

Abstract

Background

Intrinsically disordered proteins lack stable structure under physiological conditions, yet carry out many crucial biological functions, especially functions associated with regulation, recognition, signaling and control. Recently, human genetic diseases and related genes were organized into a bipartite graph (Goh KI, Cusick ME, Valle D, Childs B, Vidal M, et al. (2007) The human disease network. Proc Natl Acad Sci U S A 104: 8685–8690). This diseasome network revealed several significant features such as the common genetic origin of many diseases.

Methods and findings

We analyzed the abundance of intrinsic disorder in these diseasome network proteins by means of several prediction algorithms, and we analyzed the functional repertoires of these proteins based on prior studies relating disorder to function. Our analyses revealed that (i) Intrinsic disorder is common in proteins associated with many human genetic diseases; (ii) Different disease classes vary in the IDP contents of their associated proteins; (iii) Molecular recognition features, which are relatively short loosely structured protein regions within mostly disordered sequences and which gain structure upon binding to partners, are common in the diseasome, and their abundance correlates with the intrinsic disorder level; (iv) Some disease classes have a significant fraction of genes affected by alternative splicing, and the alternatively spliced regions in the corresponding proteins are predicted to be highly disordered; and (v) Correlations were found among the various diseasome graph-related properties and intrinsic disorder.

Conclusion

These observations provide the basis for the construction of the human-genetic-disease-associated unfoldome.