Unfoldomics of Human Genetic Diseases: Illustrative Examples of Ordered and Intrinsically Disordered Members of the Human Diseasome

Intrinsically disordered proteins (IDPs) constitute a recently recognized realm of atypical biologically active proteins that lack stable structure under physiological conditions, but are commonly involved in such crucial cellular processes as regulation, recognition, signaling and control. IDPs are very common among proteins associated with various diseases. Recently, we performed a systematic bioinformatics analysis of the human diseasome, a network that linked the human disease phenome (which includes all the human genetic diseases) with the human disease genome (which contains all the disease-related genes) (Goh, K. I., Cusick, M. E., Valle, D., Childs, B., Vidal, M., and Barabasi, A. L. (2007). The human disease network. Proc. Natl. Acad. Sci. U. S. A. 104, 8685-90). The analysis of this diseasome revealed that IDPs are abundant in proteins linked to human genetic diseases, and that different genetic disease classes varied dramatically in the IDP content (Midic U., Oldfield C. J., Dunker A. K., Obradovic Z., Uversky V. N. (2009) Protein disorder in the human diseasome: Unfoldomics of human genetic diseases. BMC Genomics. In press). Furthermore, many of the genetic disease-related proteins were shown to contain at least one molecular recognition feature, which is a relatively short loosely structured protein region within a mostly disordered segment with the feature gaining structure upon binding to a partner. Finally, alternative splicing was shown to be abundant among the diseasome genes. Based on these observations the human-genetic-disease-associated unfoldome was created. This minireview describes several illustrative examples of ordered and intrinsically disordered members of the human diseasome.