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.

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 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.

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 Unraveling the Thermodynamics of Ultra-tight Binding of Intrinsically Disordered Proteins

2021 ◽  
Vol 8 ◽  
Author(s):  
Uroš Zavrtanik ◽  
San Hadži ◽  
Jurij Lah
Keyword(s):  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Tight Binding ◽  
Bound State ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Prothymosin Α ◽  
Intrinsically Disordered ◽  
High Affinity ◽  
Entropy Optimization

Protein interactions mediated by the intrinsically disordered proteins (IDPs) are generally associated with lower affinities compared to those between globular proteins. Here, we characterize the association between the intrinsically disordered HigA2 antitoxin and its globular target HigB2 toxin from Vibrio cholerae using competition ITC experiments. We demonstrate that this interaction reaches one of the highest affinities reported for IDP-target systems (KD = 3 pM) and can be entirely attributed to a short, 20-residue-long interaction motif that folds into α-helix upon binding. We perform an experimentally based decomposition of the IDP-target association parameters into folding and binding contributions, which allows a direct comparison of the binding contribution with those from globular ultra-high affinity binders. We find that the HigA2-HigB2 interface is energy optimized to a similar extent as the interfaces of globular ultra-high affinity complexes, such as barnase-barstar. Evaluation of other ultra-high affinity IDP-target systems shows that a strategy based on entropy optimization can also achieve comparably high, picomolar affinities. Taken together, these examples show how IDP-target interactions achieve picomolar affinities either through enthalpy optimization (HigA2-HigB2), resembling the ultra-high affinity binding of globular proteins, or via bound-state fuzziness and entropy optimization (CcdA-CcdB, histone H1-prothymosin α).

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 Interaction of the C-Terminal Domains of Sendai Virus N and P Proteins: Comparison of Polymerase-Nucleocapsid Interactions within the Paramyxovirus Family

2007 ◽  
Vol 81 (13) ◽  
pp. 6807-6816 ◽  
Author(s):  
Klaartje Houben ◽  
Dominique Marion ◽  
Nicolas Tarbouriech ◽  
Rob W. H. Ruigrok ◽  
Laurence Blanchard
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Sendai Virus ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Resonance Spectroscopy ◽  
Intrinsically Disordered ◽  
Binding Interface ◽  
P Proteins ◽  
Terminal Domains

ABSTRACT Interaction of the C-terminal domains of Sendai virus (SeV) P and N proteins is crucial for RNA synthesis by correctly positioning the polymerase complex (L+P) onto the nucleocapsid (N/RNA). To better understand this mechanism within the paramyxovirus family, we have studied the complex formed by the SeV C-terminal domains of P (PX) and N (NTAIL) proteins by solution nuclear magnetic resonance spectroscopy. We have characterized SeV NTAIL, which belongs to the class of intrinsically disordered proteins, and precisely defined the binding regions within this latter domain and within PX. SeV NTAIL binds with residues 472 to 493, which have a helical propensity (residues 477 to 491) to the surface created by helices α2 and α3 of PX with a 1:1 stoichiometry, as was also found for measles virus (MV). The binding interface is dominated by charged residues, and the dissociation constant was determined to be 57 ± 18 μM under conditions of the experiment (i.e., in 0.5 M NaCl). We have also shown that the extreme C terminus of SeV NTAIL does not interact with PX, which is in contrast to MV, where a second binding site was identified. In addition, the interaction surfaces of the MV proteins are hydrophobic and a stronger binding constant was found. This gives a good illustration of how selection pressure allowed the C-terminal domains of N and P proteins to evolve concomitantly within this family of viruses in order to lead to protein complexes having the same three-dimensional fold, and thus the same function, but with completely different binding interfaces.

scholarly journals A Frustrated Binding Interface for Intrinsically Disordered Proteins

2014 ◽  
Vol 289 (9) ◽  
pp. 5528-5533 ◽  
Author(s):  
Per Jemth ◽  
Xin Mu ◽  
Åke Engström ◽  
Jakob Dogan
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Binding Interface

scholarly journals Cell cycle regulation by the intrinsically disordered proteins p21 and p27

2012 ◽  
Vol 40 (5) ◽  
pp. 981-988 ◽  
Author(s):  
Mi-Kyung Yoon ◽  
Diana M. Mitrea ◽  
Li Ou ◽  
Richard W. Kriwacki
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Bound State ◽  
Disordered Proteins ◽  
Structural Adaptation ◽  
Adaptation Mechanism ◽  
Intrinsically Disordered ◽  
Cycle Regulation

Today, it is widely accepted that proteins that lack highly defined globular three-dimensional structures, termed IDPs (intrinsically disordered proteins), play key roles in myriad biological processes. Our understanding of how intrinsic disorder mediates biological function is, however, incomplete. In the present paper, we review disorder-mediated cell cycle regulation by two intrinsically disordered proteins, p21 and p27. A structural adaptation mechanism involving a stretchable dynamic linker helix allows p21 to promiscuously recognize the various Cdk (cyclin-dependent kinase)–cyclin complexes that regulate cell division. Disorder within p27 mediates transmission of an N-terminal tyrosine phosphorylation signal to a C-terminal threonine phosphorylation, constituting a signalling conduit. These mechanisms are mediated by folding upon binding p21/p27′s regulatory targets. However, residual disorder within the bound state contributes critically to these functional mechanisms. Our studies provide insights into how intrinsic protein disorder mediates regulatory processes and opportunities for designing drugs that target cancer-associated IDPs.

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