scholarly journals Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

2021 ◽  
Vol 22 (11) ◽  
pp. 6016
Author(s):  
Niccolò Candelise ◽  
Silvia Scaricamazza ◽  
Illari Salvatori ◽  
Alberto Ferri ◽  
Cristiana Valle ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Clinical Relevance ◽  
Phenotypic Diversity ◽  
Intrinsically Disordered Protein ◽  
Structural Heterogeneity ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Β Sheet

Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

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 Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 381
Author(s):  
Bálint Mészáros ◽  
Borbála Hajdu-Soltész ◽  
András Zeke ◽  
Zsuzsanna Dosztányi
Keyword(s):  
Gene Expression Regulation ◽  
Treatment Options ◽  
Intrinsically Disordered Protein ◽  
System Level ◽  
Alternative Mechanism ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Cancer Types ◽  
Cancer Drivers

Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. These IDRs can function in multiple ways which are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks. Importantly, in certain cancer patients, mutations of disordered drivers represent key driving events. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.

scholarly journals The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

2020 ◽  
Author(s):  
Jiaxing Chen ◽  
Sofia Zaer ◽  
Paz Drori ◽  
Joanna Zamel ◽  
Khalil Joron ◽  
...  
Keyword(s):  
Single Molecule ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Intrinsically Disordered Protein ◽  
Structural Heterogeneity ◽  
Conformational Space ◽  
Conformational Ensemble ◽  
Time Resolved ◽  
Intrinsically Disordered ◽  
Transient Nature

AbstractThe intrinsically disordered protein, α-synuclein, implicated in synaptic vesicle homeostasis and neurotransmitter release, is also associated with several neurodegenerative diseases. The different roles of α-synuclein are characterized by distinct structural states (membrane-bound, dimer, tetramer, oligomer, and fibril), which are originated from its various monomeric conformations. The pathological states, determined by the ensemble of α-synuclein monomer conformations and dynamic pathways of interconversion between dominant states, remain elusive due to their transient nature. Here, we use inter-dye distance distributions from bulk time-resolved Förster resonance energy transfer as restraints in discrete molecular dynamics simulations to map the conformational space of the α-synuclein monomer. We further confirm the generated conformational ensemble in orthogonal experiments utilizing far-UV circular dichroism and cross-linking mass spectrometry. Single-molecule protein-induced fluorescence enhancement measurements show that within this conformational ensemble, some of the conformations of α-synuclein are surprisingly stable, exhibiting conformational transitions slower than milliseconds. Our comprehensive analysis of the conformational ensemble reveals essential structural properties and potential conformations that promote its various functions in membrane interaction or oligomer and fibril formation.

An intrinsically disordered protein, CP12: jack of all trades and master of the Calvin cycle

2012 ◽  
Vol 40 (5) ◽  
pp. 995-999 ◽  
Author(s):  
Brigitte Gontero ◽  
Stephen C. Maberly
Keyword(s):  
Amino Acids ◽  
Stress Responses ◽  
Intrinsically Disordered Proteins ◽  
Calvin Cycle ◽  
Intrinsically Disordered Protein ◽  
Disulfide Bridge ◽  
Co2 Assimilation ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Intrinsically Disordered

Many proteins contain disordered regions under physiological conditions and lack specific three-dimensional structure. These are referred to as IDPs (intrinsically disordered proteins). CP12 is a chloroplast protein of approximately 80 amino acids and has a molecular mass of approximately 8.2–8.5 kDa. It is enriched in charged amino acids and has a small number of hydrophobic residues. It has a high proportion of disorder-promoting residues, but has at least two (often four) cysteine residues forming one (or two) disulfide bridge(s) under oxidizing conditions that confers some order. However, CP12 behaves like an IDP. It appears to be universally distributed in oxygenic photosynthetic organisms and has recently been detected in a cyanophage. The best studied role of CP12 is its regulation of the Calvin cycle responsible for CO2 assimilation. Oxidized CP12 forms a supramolecular complex with two key Calvin cycle enzymes, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and PRK (phosphoribulokinase), down-regulating their activity. Association–dissociation of this complex, induced by the redox state of CP12, allows the Calvin cycle to be inactive in the dark and active in the light. CP12 is promiscuous and interacts with other enzymes such as aldolase and malate dehydrogenase. It also plays other roles in plant metabolism such as protecting GAPDH from inactivation and scavenging metal ions such as copper and nickel, and it is also linked to stress responses. Thus CP12 seems to be involved in many functions in photosynthetic cells and behaves like a jack of all trades as well as being a master of the Calvin cycle.

scholarly journals Investigation into Early Steps of Actin Recognition by the Intrinsically Disordered N-WASP Domain V

2019 ◽  
Vol 20 (18) ◽  
pp. 4493 ◽  
Author(s):  
Maud Chan-Yao-Chong ◽  
Dominique Durand ◽  
Tâp Ha-Duong
Keyword(s):  
Conformational Changes ◽  
Actin Polymerization ◽  
High Specificity ◽  
Physical Factors ◽  
Consensus Sequences ◽  
Recognition Process ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Dynamics Simulations ◽  
Domain V

Cellular regulation or signaling processes are mediated by many proteins which often have one or several intrinsically disordered regions (IDRs). These IDRs generally serve as binders to different proteins with high specificity. In many cases, IDRs undergo a disorder-to-order transition upon binding, following a mechanism between two possible pathways, the induced fit or the conformational selection. Since these mechanisms contribute differently to the kinetics of IDR associations, it is important to investigate them in order to gain insight into the physical factors that determine the biomolecular recognition process. The verprolin homology domain (V) of the Neural Wiskott–Aldrich Syndrome Protein (N-WASP), involved in the regulation of actin polymerization, is a typical example of IDR. It is composed of two WH2 motifs, each being able to bind one actin molecule. In this study, we investigated the early steps of the recognition process of actin by the WH2 motifs of N-WASP domain V. Using docking calculations and molecular dynamics simulations, our study shows that actin is first recognized by the N-WASP domain V regions which have the highest propensity to form transient α -helices. The WH2 motif consensus sequences “LKKV” subsequently bind to actin through large conformational changes of the disordered domain V.

scholarly journals Heme minimizes Parkinson’s disease-associated toxicity by inducing a conformational distortion in the oligomers of alpha-Synuclein

2019 ◽  
Author(s):  
Ritobrita Chakraborty ◽  
Sandip Dey ◽  
Simanta Sarani Paul ◽  
Pallabi Sil ◽  
Jayati Sengupta ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intrinsically Disordered Protein ◽  
Alpha Synuclein ◽  
Oligomeric State ◽  
Intrinsically Disordered ◽  
Nmr Study ◽  
Novel Strategy ◽  
Structural Architecture ◽  
Β Sheet

AbstractAggregation of the intrinsically disordered protein alpha-Synuclein (α-Syn) into insoluble fibrils with a cross-β sheet amyloid structure plays a key role in the neuronal pathology of Parkinson’s disease (PD). The fibrillation pathway of α-Syn encompasses a multitude of transient oligomeric forms differing in size, secondary structure, hydrophobic exposure and toxicity. According to a recent solid state NMR study, the fibrillating unit of α-Syn contains the core residues of the protein arranged into in-register parallel β sheets with a unique Greek key topology. Here, we have shown that the physiologically available small molecule heme (hemin chloride) when added at sub-stoichiometric ratios to either monomeric or aggregated α-Syn, arrests its aggregation in an oligomeric state, which is minimally toxic. Using cryo-EM, we observed that these heme-induced oligomers are ‘mace’-shaped and consist of approximately four monomers. However, the presence of a crucial twist or contortion in their Greek key structural architecture prevents further hierarchical appending into annular oligomers and protofilament formation. We confirm using a His50Gln mutant that the binding of heme onto His50 is crucial in inflicting the structural distortion and is responsible for the stabilization of the non-toxic and off-pathway α-Syn oligomers. We believe that this study provides a novel strategy of developing a therapeutic solution of PD, which has been elusive so far.

Affinity versus specificity in coupled binding and folding reactions

2019 ◽  
Author(s):  
Stefano Gianni ◽  
Per Jemth
Keyword(s):  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
High Specificity ◽  
Disordered Proteins ◽  
Protein Protein Interactions ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Interaction Interface ◽  
Disordered Regions

Abstract Intrinsically disordered protein regions may fold upon binding to an interaction partner. It is often argued that such coupled binding and folding enables the combination of high specificity with low affinity. The basic tenet is that an unfavorable folding equilibrium will make the overall binding weaker while maintaining the interaction interface. While theoretically solid, we argue that this concept may be misleading for intrinsically disordered proteins. In fact, experimental evidence suggests that interactions of disordered regions usually involve extended conformations. In such cases, the disordered region is exceptionally unlikely to fold into a bound conformation in the absence of its binding partner. Instead, these disordered regions can bind to their partners in multiple different conformations and then fold into the native bound complex, thus, if anything, increasing the affinity through folding. We concede that (de)stabilization of native structural elements such as helices will modulate affinity, but this could work both ways, decreasing or increasing the stability of the complex. Moreover, experimental data show that intrinsically disordered binding regions display a range of affinities and specificities dictated by the particular side chains and length of the disordered region and not necessarily by the fact that they are disordered. We find it more likely that intrinsically disordered regions are common in protein–protein interactions because they increase the repertoire of binding partners, providing an accessible route to evolve interactions rather than providing a stability–affinity trade-off.

scholarly journals Raman Evidence of p53-DBD Disorder Decrease upon Interaction with the Anticancer Protein Azurin

2019 ◽  
Vol 20 (12) ◽  
pp. 3078 ◽  
Author(s):  
Sara Signorelli ◽  
Salvatore Cannistraro ◽  
Anna Rita Bizzarri
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Principal Component ◽  
Intrinsically Disordered Protein ◽  
Random Coil ◽  
Disordered Proteins ◽  
Conformational Heterogeneity ◽  
Intrinsically Disordered ◽  
Tryptophan Residues ◽  
Α Helix ◽  
Β Sheet

Raman spectroscopy, which is a suitable tool to elucidate the structural properties of intrinsically disordered proteins, was applied to investigate the changes in both the structure and the conformational heterogeneity of the DNA-binding domain (DBD) belonging to the intrinsically disordered protein p53 upon its binding to Azurin, an electron-transfer anticancer protein from Pseudomonas aeruginosa. The Raman spectra of the DBD and Azurin, isolated in solution or forming a complex, were analyzed by a combined analysis based on peak inspection, band convolution, and principal component analysis (PCA). In particular, our attention was focused on the Raman peaks of Tyrosine and Tryptophan residues, which are diagnostic markers of protein side chain environment, and on the Amide I band, of which the deconvolution allows us to extract information about α-helix, β-sheet, and random coil contents. The results show an increase of the secondary structure content of DBD concomitantly with a decrease of its conformational heterogeneity upon its binding to Azurin. These findings suggest an Azurin-induced conformational change of DBD structure with possible implications for p53 functionality.

scholarly journals Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2129 ◽  
Author(s):  
Tao Zhang ◽  
Jennifer Loschwitz ◽  
Birgit Strodel ◽  
Luitgard Nagel-Steger ◽  
Dieter Willbold
Keyword(s):  
Amyloid Β ◽  
Intrinsically Disordered Protein ◽  
Amyloid Β Peptide ◽  
Amino Acid Residues ◽  
Ligand Interaction ◽  
Drug Candidates ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
First Time ◽  
Β Sheet

Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs.

scholarly journals Experimentally Determined Long Intrinsically Disordered Protein Regions Are Now Abundant in the Protein Data Bank

2020 ◽  
Vol 21 (12) ◽  
pp. 4496 ◽  
Author(s):  
Alexander Miguel Monzon ◽  
Marco Necci ◽  
Federica Quaglia ◽  
Ian Walsh ◽  
Giuseppe Zanotti ◽  
...  
Keyword(s):  
Protein Data Bank ◽  
Large Scale ◽  
Large Data ◽  
Intrinsically Disordered Protein ◽  
Data Bank ◽  
Data Sets ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Common Definition

Intrinsically disordered protein regions are commonly defined from missing electron density in X-ray structures. Experimental evidence for long disorder regions (LDRs) of at least 30 residues was so far limited to manually curated proteins. Here, we describe a comprehensive and large-scale analysis of experimental LDRs for 3133 unique proteins, demonstrating an increasing coverage of intrinsic disorder in the Protein Data Bank (PDB) in the last decade. The results suggest that long missing residue regions are a good quality source to annotate intrinsically disordered regions and perform functional analysis in large data sets. The consensus approach used to define LDRs allows to evaluate context dependent disorder and provide a common definition at the protein level.

Sign in / Sign up

Export Citation Format

Share Document