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.

scholarly journals New technologies to analyse protein function: an intrinsic disorder perspective

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 101 ◽  
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
New Technologies ◽  
Intrinsically Disordered Protein ◽  
Intrinsic Disorder ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Protein Functions ◽  
Require Structure

Functions of intrinsically disordered proteins do not require structure. Such structure-independent functionality has melted away the classic rigid “lock and key” representation of structure–function relationships in proteins, opening a new page in protein science, where molten keys operate on melted locks and where conformational flexibility and intrinsic disorder, structural plasticity and extreme malleability, multifunctionality and binding promiscuity represent a new-fangled reality. Analysis and understanding of this new reality require novel tools, and some of the techniques elaborated for the examination of intrinsically disordered protein functions are outlined in this review.

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.

Functions of short lifetime biological structures at large: the case of intrinsically disordered proteins

2018 ◽  
Author(s):  
Vladimir N Uversky
Keyword(s):  
Biological Networks ◽  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Protein Molecule ◽  
Biologically Active ◽  
Disordered Proteins ◽  
Substantial Part ◽  
Binding Modes ◽  
Intrinsically Disordered ◽  
Short Lifetime

Abstract Although for more than a century a protein function was intimately associated with the presence of unique structure in a protein molecule, recent years witnessed a skyrocket rise of the appreciation of protein intrinsic disorder concept that emphasizes the importance of the biologically active proteins without ordered structures. In different proteins, the depth and breadth of disorder penetrance are different, generating an amusing spatiotemporal heterogeneity of intrinsically disordered proteins (IDPs) and intrinsically disordered protein region regions (IDPRs), which are typically described as highly dynamic ensembles of rapidly interconverting conformations (or a multitude of short lifetime structures). IDPs/IDPRs constitute a substantial part of protein kingdom and have unique functions complementary to functional repertoires of ordered proteins. They are recognized as interaction specialists and global controllers that play crucial roles in regulation of functions of their binding partners and in controlling large biological networks. IDPs/IDPRs are characterized by immense binding promiscuity and are able to use a broad spectrum of binding modes, often resulting in the formation of short lifetime complexes. In their turn, functions of IDPs and IDPRs are controlled by various means, such as numerous posttranslational modifications and alternative splicing. Some of the functions of IDPs/IDPRs are briefly considered in this review to shed some light on the biological roles of short-lived structures at large.

scholarly journals Designing heterotropically activated allosteric conformational switches using supercharging

2020 ◽  
Vol 117 (10) ◽  
pp. 5291-5297 ◽  
Author(s):  
Peter J. Schnatz ◽  
Joseph M. Brisendine ◽  
Craig C. Laing ◽  
Bernard H. Everson ◽  
Cooper A. French ◽  
...  
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Control Mechanism ◽  
Divalent Cations ◽  
High Surface ◽  
Model Systems ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Low Concentrations

Heterotropic allosteric activation of protein function, in which binding of one ligand thermodynamically activates the binding of another, different ligand or substrate, is a fundamental control mechanism in metabolism and as such has been a long-aspired capability in protein design. Here we show that greatly increasing the magnitude of a protein’s net charge using surface supercharging transforms that protein into an allosteric ligand- and counterion-gated conformational molecular switch. To demonstrate this we first modified the designed helical bundle hemoprotein H4, creating a highly charged protein which both unfolds reversibly at low ionic strength and undergoes the ligand-induced folding transition commonly observed in signal transduction by intrinsically disordered proteins in biology. As a result of the high surface-charge density, ligand binding to this protein is allosterically activated up to 1,300-fold by low concentrations of divalent cations and the polyamine spermine. To extend this process further using a natural protein, we similarly modified Escherichia coli cytochrome b562 and the resulting protein behaves in a like manner. These simple model systems not only establish a set of general engineering principles which can be used to convert natural and designed soluble proteins into allosteric molecular switches useful in biodesign, sensing, and synthetic biology, the behavior we have demonstrated––functional activation of supercharged intrinsically disordered proteins by low concentrations of multivalent ions––may be a control mechanism utilized by Nature which has yet to be appreciated.

scholarly journals Common Functions of Disordered Proteins across Evolutionary Distant Organisms

2020 ◽  
Vol 21 (6) ◽  
pp. 2105 ◽  
Author(s):  
Arndt Wallmann ◽  
Christopher Kesten
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Plant Proteins ◽  
Sequence Structure ◽  
Intrinsically Disordered ◽  
Bioinformatic Approaches ◽  
The Common ◽  
Function Relationship

Intrinsically disordered proteins and regions typically lack a well-defined structure and thus fall outside the scope of the classic sequence–structure–function relationship. Hence, classic sequence- or structure-based bioinformatic approaches are often not well suited to identify homology or predict the function of unknown intrinsically disordered proteins. Here, we give selected examples of intrinsic disorder in plant proteins and present how protein function is shared, altered or distinct in evolutionary distant organisms. Furthermore, we explore how examining the specific role of disorder across different phyla can provide a better understanding of the common features that protein disorder contributes to the respective biological mechanism.

scholarly journals Intrinsically disordered proteins: modes of binding with emphasis on disordered domains

Open Biology ◽  
2021 ◽  
Vol 11 (10) ◽  
Author(s):  
Owen Michael Morris ◽  
James Hilary Torpey ◽  
Rivka Leah Isaacson
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Bound State ◽  
Significant Degree ◽  
Disordered Proteins ◽  
Intrinsic Properties ◽  
Static Disorder ◽  
Intrinsically Disordered ◽  
Binding Interface ◽  
Modes Of Interaction

Our notions of protein function have long been determined by the protein structure–function paradigm. However, the idea that protein function is dictated by a prerequisite complementarity of shapes at the binding interface is becoming increasingly challenged. Interactions involving intrinsically disordered proteins (IDPs) have indicated a significant degree of disorder present in the bound state, ranging from static disorder to complete disorder, termed ‘random fuzziness’. This review assesses the anatomy of an IDP and relates how its intrinsic properties permit promiscuity and allow for the various modes of interaction. Furthermore, a mechanistic overview of the types of disordered domains is detailed, while also relating to a recent example and the kinetic and thermodynamic principles governing its formation.

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.

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