uversky-IUP_ARB2008 - Intrinsically Disordered Proteins in...

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Intrinsically Disordered Proteins in Human Diseases: Introducing the D 2 Concept Vladimir N. Uversky, 1 , 2 , 3 Christopher J. Oldfeld, 1 and A. Keith Dunker 1 , 3 1 Center For Computational Biology and BioinFormatics, Department oF Biochemistry and Molecular Biology, Indiana University School oF Medicine, Indianapolis, Indiana 46202; email: [email protected]; [email protected]; [email protected] 2 Institute For Biological Instrumentation, Russian Academy oF Sciences, Pushchino, Moscow Region 142290, Russia 3 Molecular Kinetics, Inc., Indianapolis, Indiana 46268 Annu. Rev. Biophys. 2008. 37:215–46 ±irst published online as a Review in Advance on ±ebruary 4, 2008 The Annual Review of Biophysics is online at biophys.annualreviews.org This article’s doi: 10.1146/annurev.biophys.37.032807.125924 Copyright c ° 2008 by Annual Reviews. All rights reserved 1936-122X/08/0609-0215$20.00 Key Words conFormational disease, protein misFolding, intrinsic disorder Abstract Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structures under physiological conditions in vitro. They are highly abundant in nature and their Functional repertoire com- plements the Functions oF ordered proteins. IDPs are involved in regulation, signaling, and control, where binding to multiple part- ners and high-specifcity/low-aFfnity interactions play a crucial role. ±unctions oF IDPs are tuned via alternative splicing and posttransla- tional modifcations. Intrinsic disorder is a unique structural Feature that enables IDPs to participate in both one-to-many and many-to- one signaling. Numerous IDPs are associated with human diseases, including cancer, cardiovascular disease, amyloidoses, neurodegen- erative diseases, and diabetes. Overall, intriguing interconnections among intrinsic disorder, cell signaling, and human diseases suggest that protein conFormational diseases may result not only From pro- tein misFolding, but also From misidentifcation, missignaling, and unnatural or nonnative Folding. IDPs, such as α -synuclein, tau pro- tein, p53, and BRCA1, are attractive targets For drugs modulating protein-protein interactions. ±rom these and other examples, novel strategies For drug discovery based on IDPs have been developed. To summarize work in this area, we are introducing the D 2 (disorder in disorders) concept. 215 Annu. Rev. Biophys. 2008.37:215-246. Downloaded from arjournals.annualreviews.org by RIJKSUNIVERSITEIT GENT on 08/05/08. For personal use only.
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Contents INTRODUCTION. ................ 216 INTRINSICALLY DISORDERED PROTEINS AND HUMAN DISEASES: LESSONS FROM CASE STUDIES. ............... 219 α -Fetoprotein and Cancer. ....... p53 and Cancer. ................. BRCA-1 and Breast Cancer. ...... 220 α -Synuclein and Synucleinopathies. ............ A β and Tau Protein in Alzheimer’s Disease. ...................... 224 Prion Protein and Prion Diseases. ..................... Hirudin and Thrombin in Cardiovascular Disease. 225 Amylin and Type II Diabetes.
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This note was uploaded on 05/28/2010 for the course WE BIBI010000 taught by Professor Marnikvuylsteke during the Spring '10 term at Ghent University.

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uversky-IUP_ARB2008 - Intrinsically Disordered Proteins in...

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