ChemInform Abstract: Multitude of Binding Modes Attainable by Intrinsically Disordered Proteins: A Portrait Gallery of Disorder-Based Complexes

ChemInform ◽  
2011 ◽  
Vol 42 (24) ◽  
pp. no-no
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Binding Modes ◽  
Intrinsically Disordered

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 Competitive Binding of HIF-1α and CITED2 to the TAZ1 Domain of CBP from Molecular Simulations

2020 ◽  
Author(s):  
Irene Ruiz-Ortiz ◽  
David De Sancho
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Critical Role ◽  
Molecular Simulations ◽  
Bound State ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Emergent Properties ◽  
Binding Modes ◽  
Intrinsically Disordered ◽  
Transactivation Domains

<div>Many intrinsically disordered proteins (IDPs) are involved in complex signalling networks inside the cell. </div><div>Their particular binding modes elicit different types of responses and subtle regulation of biological responses. </div><div>Here we study the binding of two disordered transactivation domains from proteins HIF-1α and CITED2, whose binding to the TAZ1 domain of CBP is critical for the hypoxic response. Experiments have shown that both IDPs compete for their shared partner, and that this competition is mediated by the formation of a ternary intermediate state. Here we use molecular simulations with a coarse-grained model to provide a glimpse of the structure of this intermediate. </div><div>We find that the conserved LP(Q/E)L motif may have a critical role in the displacement of HIF-1α by CITED2 and show a possible mechanism for the transition from the intermediate to the bound state. We also explore the role of TAZ1 dynamics in the binding. The results of our simulations are consistent with many of the experimental observations and provide a detailed molecular description of the emergent properties in the complex binding of these IDPs.</div>

scholarly journals MobiDB: intrinsically disordered proteins in 2021

2020 ◽  
Vol 49 (D1) ◽  
pp. D361-D367
Author(s):  
Damiano Piovesan ◽  
Marco Necci ◽  
Nahuel Escobedo ◽  
Alexander Miguel Monzon ◽  
András Hatos ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Bound State ◽  
Disordered Proteins ◽  
Binding Modes ◽  
Data Accessibility ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Residue Contact ◽  
Recent Developments ◽  
New Statistics

Abstract The MobiDB database (URL: https://mobidb.org/) provides predictions and annotations for intrinsically disordered proteins. Here, we report recent developments implemented in MobiDB version 4, regarding the database format, with novel types of annotations and an improved update process. The new website includes a re-designed user interface, a more effective search engine and advanced API for programmatic access. The new database schema gives more flexibility for the users, as well as simplifying the maintenance and updates. In addition, the new entry page provides more visualisation tools including customizable feature viewer and graphs of the residue contact maps. MobiDB v4 annotates the binding modes of disordered proteins, whether they undergo disorder-to-order transitions or remain disordered in the bound state. In addition, disordered regions undergoing liquid-liquid phase separation or post-translational modifications are defined. The integrated information is presented in a simplified interface, which enables faster searches and allows large customized datasets to be downloaded in TSV, Fasta or JSON formats. An alternative advanced interface allows users to drill deeper into features of interest. A new statistics page provides information at database and proteome levels. The new MobiDB version presents state-of-the-art knowledge on disordered proteins and improves data accessibility for both computational and experimental users.

scholarly journals Competitive Binding of HIF-1α and CITED2 to the TAZ1 Domain of CBP from Molecular Simulations

2020 ◽  
Author(s):  
Irene Ruiz-Ortiz ◽  
David De Sancho
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Critical Role ◽  
Molecular Simulations ◽  
Bound State ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Emergent Properties ◽  
Binding Modes ◽  
Intrinsically Disordered ◽  
Transactivation Domains

<div>Many intrinsically disordered proteins (IDPs) are involved in complex signalling networks inside the cell. </div><div>Their particular binding modes elicit different types of responses and subtle regulation of biological responses. </div><div>Here we study the binding of two disordered transactivation domains from proteins HIF-1α and CITED2, whose binding to the TAZ1 domain of CBP is critical for the hypoxic response. Experiments have shown that both IDPs compete for their shared partner, and that this competition is mediated by the formation of a ternary intermediate state. Here we use molecular simulations with a coarse-grained model to provide a glimpse of the structure of this intermediate. </div><div>We find that the conserved LP(Q/E)L motif may have a critical role in the displacement of HIF-1α by CITED2 and show a possible mechanism for the transition from the intermediate to the bound state. We also explore the role of TAZ1 dynamics in the binding. The results of our simulations are consistent with many of the experimental observations and provide a detailed molecular description of the emergent properties in the complex binding of these IDPs.</div>

scholarly journals When fast is better: protein folding fundamentals and mechanisms from ultrafast approaches

2016 ◽  
Vol 473 (17) ◽  
pp. 2545-2559 ◽  
Author(s):  
Victor Muñoz ◽  
Michele Cerminara
Keyword(s):  
Protein Folding ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Binding Modes ◽  
Downhill Folding ◽  
Intrinsically Disordered ◽  
Theoretical Predictions ◽  
Underlying Mechanisms ◽  
Dynamics Simulations ◽  
New Generation

Protein folding research stalled for decades because conventional experiments indicated that proteins fold slowly and in single strokes, whereas theory predicted a complex interplay between dynamics and energetics resulting in myriad microscopic pathways. Ultrafast kinetic methods turned the field upside down by providing the means to probe fundamental aspects of folding, test theoretical predictions and benchmark simulations. Accordingly, experimentalists could measure the timescales for all relevant folding motions, determine the folding speed limit and confirm that folding barriers are entropic bottlenecks. Moreover, a catalogue of proteins that fold extremely fast (microseconds) could be identified. Such fast-folding proteins cross shallow free energy barriers or fold downhill, and thus unfold with minimal co-operativity (gradually). A new generation of thermodynamic methods has exploited this property to map folding landscapes, interaction networks and mechanisms at nearly atomic resolution. In parallel, modern molecular dynamics simulations have finally reached the timescales required to watch fast-folding proteins fold and unfold in silico. All of these findings have buttressed the fundamentals of protein folding predicted by theory, and are now offering the first glimpses at the underlying mechanisms. Fast folding appears to also have functional implications as recent results connect downhill folding with intrinsically disordered proteins, their complex binding modes and ability to moonlight. These connections suggest that the coupling between downhill (un)folding and binding enables such protein domains to operate analogically as conformational rheostats.

scholarly journals Interplay between folding and binding modulates protein sequences, structures, functions and regulation

2017 ◽  
Author(s):  
Bálint Mészáros ◽  
László Dobson ◽  
Erzsébet Fichó ◽  
Gábor E. Tusnády ◽  
Zsuzsanna Dosztányi ◽  
...  
Keyword(s):  
Structural Properties ◽  
Regulatory Networks ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Binding Modes ◽  
Sequence Structure ◽  
Binding Partner ◽  
Binding Process ◽  
Intrinsically Disordered ◽  
Protein Interactome

SummaryIntrinsically Disordered Proteins (IDPs) fulfill critical biological roles without having the potential to fold on their own. While lacking inherent structure, the majority of IDPs do reach a folded state via interaction with a protein partner, presenting a deep entanglement of the folding and binding process. Protein disorder has been recognized as a major determinant in several properties of proteins; yet the way the binding process is reflected in these features in general lacks this detail of description. Recent advances in database development enabled us to identify three basic scenarios of the interplay between folding and binding in unprecedented detail. These scenarios have fundamentally different properties in terms of protein sequence, structure, function and regulation, depending on the structural properties of the interacting partners. Strikingly, the existence of a binding partner and its structural properties influence all analyzed properties of proteins to the same extent as the divide between inherent order or disorder. The appreciation of this interplay between folding and binding is the basis for the successful charting of unknown territories in the protein interactome, the understanding of how different binding modes assemble regulatory networks, and the development of future pharmaceutical 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>

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