Medicine and Health Sciences Commons^™

Flexible Nets: Disorder And Induced Fit In The Associations Of P53 And 14-3-3 With Their Partners, Christopher J. Oldfield, Jingwei Meng, Jack Y. Yang, Mary Qu Yang, Vladimir N. Uversky, A. Keith Dunker

Molecular Medicine Faculty Publications

Background: Proteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes. Some of these proteins, called hub proteins or hubs, bind to many different protein partners. Protein intrinsic disorder, via diversity arising from structural plasticity or flexibility, provide a means for hubs to associate with many partners (Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN: Flexible Nets: The roles of intrinsic disorder in protein interaction networks. FEBS J 2005, 272:5129-5148).

Results: Here we present a detailed examination of two divergent examples: 1) p53, which uses different …

The Unfoldomics Decade: An Update On Intrinsically Disordered Proteins, A. Keith Dunker, Christopher J. Oldfield, Jingwei Meng, Pedro Romero, Jack Y. Yang, Jessica Walton Chen, Vladimir Vacic, Zoran Obradovic, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Our first predictor of protein disorder was published just over a decade ago in the Proceedings of the IEEE International Conference on Neural Networks (Romero P, Obradovic Z, Kissinger C, Villafranca JE, Dunker AK (1997) Identifying disordered regions in proteins from amino acid sequence. Proceedings of the IEEE International Conference on Neural Networks, 1: 90–95). By now more than twenty other laboratory groups have joined the efforts to improve the prediction of protein disorder. While the various prediction methodologies used for protein intrinsic disorder resemble those methodologies used for secondary structure prediction, the two types of structures are entirely different. …

Malleable Machines In Transcription Regulation: The Mediator Complex, Ágnes Tóth-Petróczy, Christopher J. Oldfield, István Simon, Yuichiro Takagi, A. Keith Dunker, Vladimir N. Uversky, Monika Fuxreiter

Molecular Medicine Faculty Publications

The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit …

A Comparative Analysis Of Viral Matrix Proteins Using Disorder Predictors, Gerard Kian-Meng Goh, A. Keith Dunker, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Background: A previous study (Goh G.K.-M., Dunker A.K., Uversky V.N. (2008) Protein intrinsic disorder toolbox for comparative analysis of viral proteins. BMC Genomics. 9 (Suppl. 2), S4) revealed that HIV matrix protein p17 possesses especially high levels of predicted intrinsic disorder (PID). In this study, we analyzed the PID patterns in matrix proteins of viruses related and unrelated to HIV-1.

Results: Both SIVmac and HIV-1 p17 proteins were predicted by PONDR VLXT to be highly disordered with subtle differences containing 50% and 60% disordered residues, respectively. SIVmac is very closely related to HIV-2. A specific region that is predicted …

Short Linear Motifs Recognized By Sh2, Sh3 And Ser/Thr Kinase Domains Are Conserved In Disordered Protein Regions, Siyun Ren, Vladimir N. Uversky, Zhengjun Chen, A. Keith Dunker, Zoran Obradovic

Molecular Medicine Faculty Publications

Background: Protein interactions are essential for most cellular functions. Interactions mediated by domains that appear in a large number of proteins are of particular interest since they are expected to have an impact on diversities of cellular processes such as signal transduction and immune response. Many well represented domains recognize and bind to primary sequences less than 10 amino acids in length called Short Linear Motifs (SLiMs).

Results: In this study, we systematically studied the evolutionary conservation of SLiMs recognized by SH2, SH3 and Ser/Thr Kinase domains in both ordered and disordered protein regions. Disordered protein regions are protein sequences …

Assessing Conservation Of Disordered Regions In Proteins, Ágnes Tóth-Petróczy, Bálint Mészáros, István Simon, A. Keith Dunker, Vladimir N. Uversky, Monika Fuxreiter

Molecular Medicine Faculty Publications

Intrinsically disordered regions (IDRs) are highly populated in eukaryotic proteomes and serve pivotal, mostly regulatory functions. Many IDRs appear to be functionally conserved and analysis of protein domains indicates high propensity of conserved regions predicted to be disordered. Nevertheless, it is difficult to assess conservation of IDRs in general due to their fast evolution and low sequence similarity. We propose three measures to evaluate conservation of IDRs: i) similarities of the disorder profiles using different prediction conditions; ii) the conservation of amino acids with propensities for promoting either disorder or order; and iii) the overlap between disordered/ordered regions. These measures …