Protein disorder in the human diseasome: Unfoldomics of human genetic diseases
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AbstractBackground: 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. © 2009 Midic et al; licensee BioMed Central Ltd.
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Has partBMC Genomics
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Unfoldomics of human diseases: Linking protein intrinsic disorder with diseasesUversky, VN; Oldfield, CJ; Midic, U; Xie, H; Xue, B; Vucetic, S; Iakoucheva, LM; Obradovic, Z; Keith, AK (2009-07-07)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. © 2009 Uversky et al; licensee BioMed Central Ltd.
A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell CultureBrown, ZZ; Akula, K; Arzumanyan, A; Alleva, J; Jackson, M; Bichenkov, E; Sheffield, JB; Feitelson, MA; Schafmeister, CE (2012-10-18)We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers . Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound 1, that binds HDM2 with a Kd value of 400 nM. The spiroligomer 1 penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner increases the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound 1 modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop. © 2012 Brown et al.