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

Research

Unfoldomics of human diseases: linking protein intrinsic disorder with diseases

Vladimir N Uversky^1,2,3 , Christopher J Oldfield¹ , Uros Midic⁴ , Hongbo Xie⁴ , Bin Xue^1,2 , Slobodan Vucetic⁴ , Lilia M Iakoucheva⁵ , Zoran Obradovic⁴ and A Keith Dunker¹

¹Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA

²Institute for Intrinsically Disordered Protein Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA

³Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

⁴Center for Information Science and Technology, Temple University, Philadelphia, PA 19122, USA

⁵Laboratory of Statistical Genetics, The Rockefeller University, New York, NY 10065 USA

author email corresponding author email

BMC Genomics 2009, 10(Suppl 1):S7doi:10.1186/1471-2164-10-S1-S7

Published:	7 July 2009

Abstract

Background

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) lack stable tertiary and/or secondary structure yet fulfills key biological functions. The recent recognition of IDPs and IDRs is leading to an entire field aimed at their systematic structural characterization and at determination of their mechanisms of action. Bioinformatics studies showed that IDPs and IDRs are highly abundant in different proteomes and carry out mostly regulatory functions related to molecular recognition and signal transduction. These activities complement the functions of structured proteins. IDPs and IDRs were shown to participate in both one-to-many and many-to-one signaling. Alternative splicing and posttranslational modifications are frequently used to tune the IDP functionality. Several individual IDPs were shown to be associated with human diseases, such as cancer, cardiovascular disease, amyloidoses, diabetes, neurodegenerative diseases, and others. This raises questions regarding the involvement of IDPs and IDRs in various diseases.

Results

IDPs and IDRs were shown to be highly abundant in proteins associated with various human maladies. As the number of IDPs related to various diseases was found to be very large, the concepts of the disease-related unfoldome and unfoldomics were introduced. Novel bioinformatics tools were proposed to populate and characterize the disease-associated unfoldome. Structural characterization of the members of the disease-related unfoldome requires specialized experimental approaches. IDPs possess a number of unique structural and functional features that determine their broad involvement into the pathogenesis of various diseases.

Conclusion

Proteins associated with various human diseases are enriched in intrinsic disorder. These disease-associated IDPs and IDRs are real, abundant, diversified, vital, and dynamic. These proteins and regions comprise the disease-related unfoldome, which covers a significant part of the human proteome. Profound association between intrinsic disorder and various human diseases is determined by a set of unique structural and functional characteristics of IDPs and IDRs. Unfoldomics of human diseases utilizes unrivaled bioinformatics and experimental techniques, paves the road for better understanding of human diseases, their pathogenesis and molecular mechanisms, and helps develop new strategies for the analysis of disease-related proteins.