scholarly journals The case for intrinsically disordered proteins playing contributory roles in molecular recognition without a stable 3D structure

10.3410/b5-1 ◽  
2013 ◽  
Vol 5 ◽  
Author(s):  
Vladimir N. Uversky ◽  
A. Keith Dunker
Keyword(s):  
Molecular Recognition ◽  
Intrinsically Disordered Proteins ◽  
3D Structure ◽  
Disordered Proteins ◽  
Intrinsically Disordered

scholarly journals Intrinsically Disordered Proteins in Chronic Diseases

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 147 ◽  
Author(s):  
Prakash Kulkarni ◽  
Vladimir Uversky
Keyword(s):  
Chronic Diseases ◽  
Intrinsically Disordered Proteins ◽  
Large Fraction ◽  
3D Structure ◽  
Human Proteome ◽  
Disordered Proteins ◽  
3D Structures ◽  
Physiological Conditions ◽  
Intrinsically Disordered

It is now increasingly evident that a large fraction of the human proteome comprises proteins that, under physiological conditions, lack fixed, ordered 3D structures as a whole or have segments that are not likely to form a defined 3D structure [...]

scholarly journals Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

2019 ◽  
Vol 28 (11) ◽  
pp. 1952-1965 ◽  
Author(s):  
Jing Yang ◽  
Meng Gao ◽  
Junwen Xiong ◽  
Zhengding Su ◽  
Yongqi Huang
Keyword(s):  
Molecular Recognition ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered

scholarly journals Promising Drug Design Strategies: Intrinsically Disordered Proteins

2020 ◽  
Vol 3 (2) ◽  
Author(s):  
Michaux C
Keyword(s):  
Drug Design ◽  
Protein Sequence ◽  
Intrinsically Disordered Proteins ◽  
3D Structure ◽  
Three Dimensional ◽  
Disordered Proteins ◽  
Design Strategies ◽  
Intrinsically Disordered ◽  
Associated Function

In contrast to the classical paradigm “one sequence - one structure - one function” that a given protein sequence corresponds to a well-defined three-dimensional (3D) structure and an associated function, it was discovered in the 1990s that an increasing number of proteins can be functional in the absence of a stable 3D-structure.

scholarly journals Exploring Energy Landscapes of Intrinsically Disordered Proteins: Insights into Functional Mechanisms

2021 ◽  
Author(s):  
Antonio B. Oliveira ◽  
Xingcheng Lin ◽  
Prakash Kulkarni ◽  
José N. Onuchic ◽  
Susmita Roy ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Energy Landscape ◽  
3D Structure ◽  
Intrinsically Disordered Protein ◽  
Terminal Segment ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Energy Landscapes ◽  
Reaction Coordinates ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) lack a rigid 3D structure and populate a polymorphic ensemble of conformations. Because of the lack of a reference conformation, their energy landscape representation in terms of reaction coordinates presents a daunting challenge. Here, our newly developed Energy Landscape Visualization Method (ELViM), a reaction coordinate-free approach, shows its prime application to explore frustrated energy landscapes of an intrinsically disordered protein, Prostate-Associated Gene 4 (PAGE4). PAGE4 is a transcriptional coactivator that potentiates the oncogene c-Jun. Two kinases, namely HIPK1 and CLK2, phosphorylate PAGE4 generating variants phosphorylated at different serine/threonine residues (HIPK1-PAGE4 and CLK2-PAGE4, respectively) with opposing functions. While HIPK1-PAGE4 predominantly phosphorylates Thr51 and potentiates c-Jun, CLK2-PAGE4 hyper-phosphorylates PAGE4 and attenuates transactivation. To understand the underlying mechanisms of conformational diversity among different phosphoforms, we have analyzed their atomistic trajectories simulated using AWSEM forcefield and the energy landscapes were elucidated using ELViM. This method allows us to identify and compare the population distributions of different conformational ensembles of PAGE4 phosphoforms using the same effective phase space. The results reveal a predominant conformational ensemble with an extended C-terminal segment of WT PAGE4, which exposes a functional residue Thr51, implying its potential of undertaking a fly-casting mechanism while binding to its cognate partner. In contrast, for HIPK1-PAGE4, a compact conformational ensemble enhances its population sequestering phosphorylated-Thr51. This clearly explains the experimentally observed weaker affinity of HIPK1-PAGE4 for c-Jun. ELViM appears as a powerful tool especially to analyze the highly-frustrated energy landscape representation of IDPs where appropriate reaction coordinates are hard to apprehend.

scholarly journals Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

2017 ◽  
Vol 114 (13) ◽  
pp. E2644-E2653 ◽  
Author(s):  
Prakash Kulkarni ◽  
Mohit Kumar Jolly ◽  
Dongya Jia ◽  
Steven M. Mooney ◽  
Ajay Bhargava ◽  
...  
Keyword(s):  
Single Molecule ◽  
Intrinsically Disordered Proteins ◽  
Large Fraction ◽  
Conformational Dynamics ◽  
3D Structure ◽  
Random Coil ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Intrinsically Disordered ◽  
Androgen Independent

Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. Prostate-Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. Homeodomain-Interacting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgen-dependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgen-dependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.

scholarly journals Physical Background of the Disordered Nature of “Mutual Synergetic Folding” Proteins

2018 ◽  
Vol 19 (11) ◽  
pp. 3340 ◽  
Author(s):  
Csaba Magyar ◽  
Anikó Mentes ◽  
Erzsébet Fichó ◽  
Miklós Cserző ◽  
István Simon
Keyword(s):  
Contact Surface ◽  
Driving Force ◽  
Structural Variation ◽  
Intrinsically Disordered Proteins ◽  
Main Chain ◽  
Protein Complexes ◽  
3D Structure ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Physical Background

Intrinsically disordered proteins (IDPs) lack a well-defined 3D structure. Their disordered nature enables them to interact with several other proteins and to fulfil their vital biological roles, in most cases after coupled folding and binding. In this paper, we analyze IDPs involved in a new mechanism, mutual synergistic folding (MSF). These proteins define a new subset of IDPs. Recently we collected information on these complexes and created the Mutual Folding Induced by Binding (MFIB) database. These protein complexes exhibit considerable structural variation, and almost half of them are homodimers, but there is a significant amount of heterodimers and various kinds of oligomers. In order to understand the basic background of the disordered character of the monomers found in MSF complexes, the simplest part of the MFIB database, the homodimers are analyzed here. We conclude that MFIB homodimeric proteins have a larger solvent-accessible main-chain surface area on the contact surface of the subunits, when compared to globular homodimeric proteins. The main driving force of the dimerization is the mutual shielding of the water-accessible backbones and the formation of extra intermolecular interactions.

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