Dimerization underlies the aggregation propensity of intrinsically disordered CCDC124

2021 ◽  
Author(s):  
Merve Tuzlakoğlu Öztürk ◽  
Ömer Güllülü
Keyword(s):  
Aggregation Propensity ◽  
Intrinsically Disordered

Current Challenges and Limitations in the Studies of Intrinsically Disordered Proteins in Neurodegenerative Diseases by Computer Simulations

2020 ◽  
Vol 17 ◽  
Author(s):  
Ibrahim Yagiz Akbayrak ◽  
Sule Irem Caglayan ◽  
Zilan Ozcan ◽  
Vladimir N. Uversky ◽  
Orkid Coskuner-Weber
Keyword(s):  
Neurodegenerative Diseases ◽  
Computer Simulations ◽  
Conformational Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Computational Studies ◽  
Accurate Data ◽  
Aggregation Propensity ◽  
Intrinsically Disordered ◽  
Future Developments

: Experiments face challenges in the analysis of intrinsically disordered proteins in solution due to fast conformational changes and enhanced aggregation propensity. Computational studies complement experiments, being widely used in the analyses of intrinsically disordered proteins, especially those positioned at the centers of neurodegenerative diseases. However, recent investigations – including our own – revealed that computer simulations face significant challenges and limitations themselves. In this review, we introduced and discussed some of the scientific challenges and limitations of computational studies conducted on intrinsically disordered proteins. We also outlined the importance of future developments in the areas of computational chemistry and computational physics that would be needed for generating more accurate data for intrinsically disordered proteins from computer simulations. Additional theoretical strategies that can be developed are discussed herein.

scholarly journals Extent of N-terminus exposure by altered long-range interactions of monomeric alpha-synuclein determines its aggregation propensity

2019 ◽  
Author(s):  
Amberley D. Stephens ◽  
Maria Zacharopoulou ◽  
Rani Moons ◽  
Giuliana Fusco ◽  
Neeleema Seetaloo ◽  
...  
Keyword(s):  
Long Range ◽  
Intrinsically Disordered Protein ◽  
Local Environment ◽  
Alpha Synuclein ◽  
Conformational Space ◽  
Conformational Ensemble ◽  
Aggregation Propensity ◽  
Intrinsically Disordered ◽  
Long Range Interactions ◽  
N Terminus

AbstractAs an intrinsically disordered protein, monomeric alpha synuclein (aSyn) constantly reconfigures and probes the conformational space. Long-range interactions across the protein maintain its solubility and mediate this dynamic flexibility, but also provide residual structure. Certain conformations lead to aggregation prone and non-aggregation prone intermediates, but identifying these within the dynamic ensemble of monomeric conformations is difficult. Herein, we used the biologically relevant calcium ion to investigate the conformation of monomeric aSyn in relation to its aggregation propensity. By using calcium to perturb the conformational ensemble, we observe differences in structure and intra-molecular dynamics between two aSyn C-terminal variants, D121A and pS129, and the aSyn familial disease mutants, A30P, E46K, H50Q, G51D, A53T and A53E, compared to wild-type (WT) aSyn. We observe that the more exposed the N-terminus and the beginning of the NAC region are, the more aggregation prone monomeric aSyn conformations become. N-terminus exposure occurs upon release of C-terminus interactions when calcium binds, but the level of exposure is specific to the aSyn mutation present. There was no correlation between single charge alterations, calcium affinity, or the number of ions bound on aSyn’s aggregation propensity, indicating that sequence or post-translation modification (PTM)-specific conformational differences between the N- and C-termini and the specific local environment mediate aggregation propensity instead. Understanding aggregation prone conformations of monomeric aSyn and the environmental conditions they form under will allow us to design new therapeutics targeted to the monomeric protein, to stabilise aSyn in non-aggregation prone conformations, by either preserving long-range interactions between the N- and C-termini or by protecting the N-terminus from exposure.

scholarly journals Mechanistic Insights on ATP’s role as Hydrotrope

2021 ◽  
Author(s):  
Susmita Sarkar ◽  
Jagannath Mondal
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Polymer Surface ◽  
Disordered Proteins ◽  
Aggregation Process ◽  
Single Chain ◽  
Aggregation Propensity ◽  
Intrinsically Disordered ◽  
Amphiphilic Molecules ◽  
Preferential Binding ◽  
Self Aggregation

AbstractHydrotropes are small amphiphilic molecules which help in solubilizing hydrophobic entities in aqueous medium. Recent experimental investigation has provided convincing evidences that, adenosine triphosphate (ATP), besides being an energy currency of cell, also can act as hydrotrope to inhibit the formation of protein condensates. In this work, we have designed computer simulations of prototypical macromolecules in aqueous ATP solution to dissect the molecular mechanism underlying ATP’s newly discovered role as a hydrotrope. The simulation demonstrates that ATP can unfold a single-chain of hydrophobic macromolecule as well as can disrupt the aggregation process of a hydrophobic assembly. Moreover, the introduction of charges in the macromolecule is found to reinforce ATP’s disaggregation effects in a synergistic fashion, a behaviour reminiscent of recent experimental observation of pronounced hydrotropic action of ATP in intrinsically disordered proteins. A molecular analysis indicates that this new-found ability of ATP are ingrained in its propensity of preferential binding to the polymer surface, which gets fortified in presence of charges. The investigation also renders evidence that the key to the ATP’s superior hydrotropic role over chemical hydrotrope (Sodium xylene sulfonate, NaXS) may lie in its inherent self-aggregation propensity. Overall, via employing a bottom-up approach the current investigation provides fresh mechanistic insights into the dual solubilizing and denaturing abilities of ATP.

Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins

2020 ◽  
Vol 477 (7) ◽  
pp. 1219-1225 ◽  
Author(s):  
Nikolai N. Sluchanko
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Major Protein ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Biochemical Journal ◽  
Multiple Binding ◽  
And Control

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain

2018 ◽  
Author(s):  
Sarah Klass ◽  
Matthew J. Smith ◽  
Tahoe Fiala ◽  
Jessica Lee ◽  
Anthony Omole ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fusion Proteins ◽  
Organic Molecules ◽  
Intrinsically Disordered Protein ◽  
Protein Domain ◽  
Enzymatic Cleavage ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Self Assembling ◽  
Protein Tag

Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values below 1 µM being observed in some cases. The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications.

Sequence Specificity Despite Intrinsic Disorder: How a Disease-Associated Val/Met Polymorphism Shifts Tertiary Interactions in a Long Disordered Protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Secondary Structure ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Heterogeneous Polymer ◽  
Non Local ◽  
Dynamics Simulations

<div>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) encodes a hydrophobic-to-hydrophobic mutation at the midpoint of the prodomain of precursor brain-derived neurotrophic factor (BDNF), one of the earliest SNPs to be associated with neuropsychiatric disorders, for which the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence.</div><div>The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the local structure change is mediated via entropic and sequence specific effects. We show that the highly disordered prodomain can be meaningfully divided into domains based on sequence alone. Monte Carlo simulations of a self-excluding heterogeneous polymer, with monomers representing each domain, suggest the sequence would be effectively segmented by the long, highly disordered polyampholyte near the sequence midpoint. This is qualitatively consistent with observed interdomain contacts within the BDNF prodomain, although contacts between the two segments are enriched relative to the self-excluding polymer. The Val66Met mutation increases interactions across the boundary between the two segments, due in part to a specific Met-Met interaction with a Methionine in the other segment. This effect propagates to cause the non-local change in secondary structure around the second methionine, previously observed in NMR. The effect is not mediated simply via changes in inter-domain contacts but is also dependent on secondary structure formation around residue 66, indicating a mechanism for secondary structure coupling in disordered proteins. </div>

Association/dissociation Mechanisms of Intrinsically Disordered Region of Protein Beyond Conformational Selection and Induced Fit

2019 ◽  
Author(s):  
Duy Phuoc Tran ◽  
Akio Kitao
Keyword(s):  
Free Energy ◽  
Transcriptional Activation ◽  
Binding Free Energy ◽  
Energy Structure ◽  
Induced Fit ◽  
Hydrogen Bond Formation ◽  
Conformational Selection ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region ◽  
Dissociation Mechanisms

<p>We investigate association and dissociation mechanisms of a typical intrinsically disordered region (IDR), transcriptional activation subdomain of tumor repressor protein p53 (TAD-p53) with murine double-minute clone 2 protein (MDM2). Using the combination of cycles of association and dissociation parallel cascade molecular dynamics, multiple standard MD, and Markov state model, we are successful in obtaining the lowest free energy structure of MDM2/TAD-p53 complex as the structure very close to that in crystal without prior knowledge. This method also reproduces the experimentally measured standard binding free energy, and association and dissociation rate constants solely with the accumulated MD simulation cost of 11.675 μs, in spite of the fact that actual dissociation occurs in the order of a second. Although there exist a few complex intermediates with similar free energies, TAD-p53 first binds MDM2 as the second lowest free energy intermediate dominantly (> 90% in flux), taking a form similar to one of the intermediate structures in its monomeric state. The mechanism of this step has a feature of conformational selection. In the second step, dehydration of the interface, formation of π-π stackings of the side-chains, and main-chain relaxation/hydrogen bond formation to complete α-helix take place, showing features of induced fit. In addition, dehydration (dewetting) is a key process for the final relaxation around the complex interface. These results demonstrate a more fine-grained view of the IDR association/dissociation beyond classical views of protein conformational change upon binding.</p>

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