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 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.

NMR Spectroscopic Studies of Intrinsically Disordered Proteins at Near-Physiological Conditions

2013 ◽  
Vol 125 (45) ◽  
pp. 12024-12028 ◽  
Author(s):  
Sergio Gil ◽  
Tomáš Hošek ◽  
Zsofia Solyom ◽  
Rainer Kümmerle ◽  
Bernhard Brutscher ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Spectroscopic Studies ◽  
Disordered Proteins ◽  
Physiological Conditions ◽  
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 Hierarchical Ensembles of Intrinsically Disordered Proteins at Atomic Resolution in Molecular Dynamics Simulations

2019 ◽  
Author(s):  
Lisa M. Pietrek ◽  
Lukas S. Stelzl ◽  
Gerhard Hummer
Keyword(s):  
Molecular Dynamics ◽  
Local Structure ◽  
High Performance ◽  
Intrinsically Disordered Proteins ◽  
Large Fraction ◽  
Conformational Dynamics ◽  
Full Length ◽  
Atomic Resolution ◽  
Disordered Proteins ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) constitute a large fraction of the human proteome and are critical in the regulation of cellular processes. A detailed understanding of the conformational dynamics of IDPs could help to elucidate their roles in health and disease. However the inherent flexibility of IDPs makes structural studies and their interpretation challenging. Molecular dynamics (MD) simulations could address this challenge in principle, but inaccuracies in the simulation models and the need for long simulations have stymied progress. To overcome these limitations, we adopt an hierarchical approach that builds on the “flexible meccano” model of Bernadó et al. (J. Am. Chem. Soc. 2005, 127, 17968-17969). First, we exhaustively sample small IDP fragments in all-atom simulations to capture local structure. Then, we assemble the fragments into full-length IDPs to explore the stereochemically possible global structures of IDPs. The resulting ensembles of three-dimensional structures of full-length IDPs are highly diverse, much more so than in standard MD simulation. For the paradigmatic IDP α-synuclein, our ensemble captures both local structure, as probed by nuclear magnetic resonance (NMR) spectroscopy, and its overall dimension, as obtained from small-angle X-ray scattering (SAXS) in solution. By generating representative and meaningful starting ensembles, we can begin to exploit the massive parallelism afforded by current and future high-performance computing resources for atomic-resolution characterization of IDPs.

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 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.

scholarly journals Effect of Disease Causing Missense Mutations on Intrinsically Disordered Regions in Proteins

2021 ◽  
Author(s):  
Suryanarayana Seera ◽  
H.A. Nagarajaram
Keyword(s):  
Intrinsically Disordered Proteins ◽  
High Energy ◽  
Disordered Proteins ◽  
Missense Mutations ◽  
Local Minima ◽  
3D Structures ◽  
Functional Roles ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Regions

AbstractIt is well known that disease-causing missense mutations (DCMMs) reduce the structural stability/integrity of the proteins with well-defined 3D structures thereby impacting their molecular functions. However, it is not known in what way DCMMs affect the intrinsically disordered proteins (IDPs) that do not adopt well defined stable 3D structures. In order to investigate how DCMMs may impact intrinsically disordered regions (IDRs) in proteins we undertook Molecular Dynamics (MD) based studies on three different examples of functionally important IDRs with known DCMMs. Our studies revealed that the functional impact of DCMMs is in reducing the conformational heterogeneity of IDRs which is intrinsic and quintessential for their multi-faceted cellular roles. These results are reinforced by energy landscapes of the wildtype and mutant IDRs where the former is characterized by many local minima separated by low barriers whereas the latter are characterized by one global minimum and several local minima separated by high energy barriers. Our MD based studies also indicate that DCMMs stabilize a very few structural possibilities of IDRs either by the newly formed interactions induced by the substituted side chains or by means of restricted or increased flexibilities of the backbone conformations at the mutation sites. Furthermore, the structural possibilities stabilized by DCMMs do not support the native functional roles of the IDRs thereby leading to disease conditions.

scholarly journals Mechanistic insights from replica exchange molecular dynamics simulations into mutation induced disordered-to-ordered transition in Hahellin, a βγ-crystallin

2018 ◽  
Author(s):  
Sunita Patel ◽  
Bal Krishnan ◽  
Ramakrishna V. Hosur ◽  
Kandala V. R. Chary
Keyword(s):  
Molecular Dynamics ◽  
Intrinsically Disordered Proteins ◽  
Conformational Transition ◽  
3D Structure ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Replica Exchange ◽  
Replica Exchange Molecular Dynamics ◽  
Intrinsically Disordered ◽  
Dynamics Simulations

AbstractIntrinsically disordered proteins (IDPs) form a special category because they lack a unique well-folded 3D structure under physiological conditions. They play crucial role in cell signaling, regulatory functions and responsible for several diseases. Although, they are abundant in nature, only a small fraction of it has been characterized till date. Such proteins adopt a range of conformations and can undergo transformation from disordered-to-ordered state or vice-versa upon binding to ligand. Insights of such conformational transition is perplexing in several cases. In the present study, we characterized disordered as well as ordered states and the factors contributing the transitions through a mutational study by employing replica exchange molecular dynamics simulation on a βγ-crystallin. Most of the proteins within this superfamily are inherently ordered. However, Hahellin, although a member of βγ-crystallin, it is intrinsically disordered in its apo-form which takes a well-ordered βγ-crystallin fold upon binding to Ca2+. It is intriguing that the mutation at the 5th position of the canonical motif to Arg increases the domain stability in several ordered microbial βγ-crystallins with concomitant loss in Ca2+ binding affinity. We carried out similar Ser to Arg mutations at 5th position of the canonical motif for the first time in an intrinsically disordered protein to understand the mechanistic insights of conformational transition. Our study revealed that newly formed ionic and hydrogen bonding interactions at the canonical Ca2+ binding sites play crucial role in transforming the disordered conformation into ordered βγ-crystallin.Author summaryIntrinsically disordered proteins lack a unique ordered 3D structure under physiological condition. Although, they are abundant in nature, only a small fraction of these proteins has been characterized till date due to adaptation of multiple conformations and methodological limitation. βγ-crystallins are inherently ordered, however recently a small number of proteins within this superfamily have been identified as intrinsically disordered protein. Hahellin is one such protein which is intrinsically disordered in its apo-form but takes a well-ordered βγ-crystallin fold upon binding to Ca2+. In the present study, we decipher the underlying mechanism of disordered-to-ordered transition in Hahellin by mutations, employing replica exchange molecular dynamics simulations. Earlier experimental studies reported an increase in stabilization of the ordered βγ-crystallion upon mutation to Arg at 5th position of the canonical Ca2+ binding motifs, N/D-N/D-X1-X2-S/T-S. We performed similar Ser to Arg mutation in an intrinsically disordered Hahellin to get the mechanistic insights of the conformational transition in the absence of Ca2+. Our study revealed that several newly formed ionic and hydrogen bonding interactions contributed by the mutant residues are responsible for both intra- and inter-motif rigidification, resulting in overall stability of βγ-crystallin domain.

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