scholarly journals Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies

2019 ◽  
Vol 20 (6) ◽  
pp. 1322 ◽  
Author(s):  
Anne Martinelli ◽  
Fernanda Lopes ◽  
Elisa John ◽  
Célia Carlini ◽  
Rodrigo Ligabue-Braun
Keyword(s):  
Neurodegenerative Diseases ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Future Developments ◽  
Regulatory Metabolism ◽  
Eukaryotic Genomes ◽  
New Strategies

Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer′s, Parkinson′s, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the “IDP-like” PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases.

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.

IDENTIFICATION OF THE POTENTIAL RNA EDITING SITES FOR GENES OF INTRINSICALLY DISORDERED PROTEINS ASSOCIATED WITH NEURODEGENERATIVE DISEASES

2020 ◽  
pp. 104-106
Author(s):  
M. Medvedeva ◽  
V. Muronetz
Keyword(s):  
Neurodegenerative Diseases ◽  
Cell Line ◽  
Rna Editing ◽  
Intrinsically Disordered Proteins ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Unfolded Proteins ◽  
Adenosine Deaminases ◽  
Intrinsically Disordered

A search for genes of naturally unfolded proteins associated with neurodegeneration containing tyrosine codons with the potential for editing RNA by adenosine deaminases was performed, and such sites were tested for the alpha - synuclein gene in the SH-SY5Y cell line.

From folding to function: complex macromolecular reactions unraveled one-by-one with optical tweezers

2021 ◽  
Author(s):  
Pétur O. Heidarsson ◽  
Ciro Cecconi
Keyword(s):  
Optical Tweezers ◽  
Single Molecule ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Conformational Dynamics ◽  
Disordered Proteins ◽  
Kinase Activation ◽  
Intrinsically Disordered ◽  
Complex Protein ◽  
Methodological Principles

Abstract Single-molecule manipulation with optical tweezers has uncovered macromolecular behaviour hidden to other experimental techniques. Recent instrumental improvements have made it possible to expand the range of systems accessible to optical tweezers. Beyond focusing on the folding and structural changes of isolated single molecules, optical tweezers studies have evolved into unraveling the basic principles of complex molecular processes such as co-translational folding on the ribosome, kinase activation dynamics, ligand–receptor binding, chaperone-assisted protein folding, and even dynamics of intrinsically disordered proteins (IDPs). In this mini-review, we illustrate the methodological principles of optical tweezers before highlighting recent advances in studying complex protein conformational dynamics – from protein synthesis to physiological function – as well as emerging future issues that are beginning to be addressed with novel approaches.

scholarly journals Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jing Li ◽  
Jordan T White ◽  
Harry Saavedra ◽  
James O Wrabl ◽  
Hesam N Motlagh ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Control Function ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Novel Strategy ◽  
Structured Proteins

Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here, we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of ‘energetic frustration’. We demonstrate that human glucocorticoid receptor tunes this signaling in vivo by producing translational isoforms differing only in the length of the disordered region, which modulates the degree of frustration. We expect this frustration-based model of allostery will prove to be generally important in explaining signaling in other IDPs.

scholarly journals Temperature-dependent structural changes in intrinsically disordered proteins: Formation of α-helices or loss of polyproline II?

2010 ◽  
Vol 19 (8) ◽  
pp. 1555-1564 ◽  
Author(s):  
Magnus Kjaergaard ◽  
Ann-Beth Nørholm ◽  
Ruth Hendus-Altenburger ◽  
Stine F. Pedersen ◽  
Flemming M. Poulsen ◽  
...  
Keyword(s):  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Temperature Dependent ◽  
Intrinsically Disordered ◽  
Polyproline Ii

scholarly journals Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology

2019 ◽  
Vol 20 (1) ◽  
pp. 141 ◽  
Author(s):  
Francesca Longhena ◽  
Gaia Faustini ◽  
Maria Grazia Spillantini ◽  
Arianna Bellucci
Keyword(s):  
Lipid Membranes ◽  
Intrinsically Disordered Proteins ◽  
Lipid Membrane ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Monoamine Transporters ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Multiple Partners

Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disordered proteins (IDPs) family. As with many other IDPs, α-syn is considered a hub protein. This function is particularly relevant at synaptic sites, where α-syn is abundant and interacts with many partners, such as monoamine transporters, cytoskeletal components, lipid membranes, chaperones and synaptic vesicles (SV)-associated proteins. These protein–protein and protein–lipid membrane interactions are crucial for synaptic functional homeostasis, and alterations in α-syn can cause disruption of this complex network, and thus a failure of the synaptic machinery. Alterations of the synaptic environment or post-translational modification of α-syn can induce its misfolding, resulting in the formation of oligomers or fibrillary aggregates. These α-syn species are thought to play a pathological role in neurodegenerative disorders with α-syn deposits such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are referred to as synucleinopathies. Here, we aim at revising the complex and promiscuous role of α-syn at synaptic terminals in order to decipher whether α-syn molecular interactants may influence its conformational state, contributing to its aggregation, or whether they are just affected by it.

scholarly journals Salient Features of Monomeric Alpha-Synuclein Revealed by NMR Spectroscopy

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 428
Author(s):  
Do-Hyoung Kim ◽  
Jongchan Lee ◽  
K. Mok ◽  
Jung Lee ◽  
Kyou-Hoon Han
Keyword(s):  
Structural Biology ◽  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Strongly Correlated ◽  
Proper Understanding ◽  
Intrinsically Disordered ◽  
Structural Details ◽  
The One

Elucidating the structural details of proteins is highly valuable and important for the proper understanding of protein function. In the case of intrinsically disordered proteins (IDPs), however, obtaining the structural details is quite challenging, as the traditional structural biology tools have only limited use. Nuclear magnetic resonance (NMR) is a unique experimental tool that provides ensemble conformations of IDPs at atomic resolution, and when studying IDPs, a slightly different experimental strategy needs to be employed than the one used for globular proteins. We address this point by reviewing many NMR investigations carried out on the α-synuclein protein, the aggregation of which is strongly correlated with Parkinson’s disease.

Intrinsically disordered proteins: administration not executive

2012 ◽  
Vol 40 (5) ◽  
pp. 945-949 ◽  
Author(s):  
Mike P. Williamson ◽  
Jennifer R. Potts
Keyword(s):  
Executive Functions ◽  
Intrinsically Disordered Proteins ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Pharmaceutical Intervention ◽  
Intrinsically Disordered ◽  
Good Target ◽  
Eukaryotic Genomes

IDPs (intrinsically disordered proteins) are common in eukaryotic genomes and have regulatory roles. In the cell, they are disordered, although not completely random. They bind weakly, but specifically, often remaining partially disordered even when bound. Whereas folded globular proteins have ‘executive’ roles in the cell, IDPs have an essential administrative function, making sure that the executive functions are properly co-ordinated. This makes them a good target for pharmaceutical intervention.

scholarly journals Affinity of IDPs to their targets is modulated by ion-specific changes in kinetics and residual structure

2017 ◽  
Vol 114 (37) ◽  
pp. 9882-9887 ◽  
Author(s):  
Basile I. M. Wicky ◽  
Sarah L. Shammas ◽  
Jane Clarke
Keyword(s):  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Marginal Stability ◽  
Residual Structure ◽  
Intrinsically Disordered ◽  
Folded Proteins ◽  
The Stability ◽  
Ion Profiles

Intrinsically disordered proteins (IDPs) are characterized by a lack of defined structure. Instead, they populate ensembles of rapidly interconverting conformations with marginal structural stabilities. Changes in solution conditions such as temperature and crowding agents consequently affect IDPs more than their folded counterparts. Here we reveal that the residual structure content of IDPs is modulated both by ionic strength and by the type of ions present in solution. We show that these ion-specific structural changes result in binding affinity shifts of up to sixfold, which happen through alteration of both association and dissociation rates. These effects follow the Hofmeister series, but unlike the well-established effects on the stability of folded proteins, they already occur at low, hypotonic concentrations of salt. We attribute this sensitivity to the marginal stability of IDPs, which could have physiological implications given the role of IDPs in signaling, the asymmetric ion profiles of different cellular compartments, and the role of ions in biology.

Sign in / Sign up

Export Citation Format

Share Document