scholarly journals The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins

2019 ◽  
Vol 20 (21) ◽  
pp. 5501 ◽  
Author(s):  
Izzy Owen ◽  
Frank Shewmaker
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Genomics And Proteomics ◽  
Eukaryotic Proteomes

Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions. Here, we discuss how post-translational modifications of intrinsically disordered protein segments can regulate the molecular condensation of macromolecules into functional phase-separated complexes.

scholarly journals Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation

2019 ◽  
Vol 116 (41) ◽  
pp. 20446-20452 ◽  
Author(s):  
Utsab R. Shrestha ◽  
Puneet Juneja ◽  
Qiu Zhang ◽  
Viswanathan Gurumoorthy ◽  
Jose M. Borreguero ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Intrinsically Disordered Proteins ◽  
Chemical Shifts ◽  
Intrinsically Disordered Protein ◽  
Physical Models ◽  
Dynamics Simulation ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteomes ◽  
Heterogeneous Ensemble

Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.

scholarly journals Progressive Phosphorylation Modulates the Self-Association of a Variably Modified Histone H3 Peptide

2021 ◽  
Vol 8 ◽  
Author(s):  
George V. Papamokos ◽  
George Tziatzos ◽  
Dimitrios G. Papageorgiou ◽  
Spyros Georgatos ◽  
Efthimios Kaxiras ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Histone H3 ◽  
Intramolecular Interactions ◽  
Disordered Proteins ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Self Association ◽  
Dynamics Simulations ◽  
Peptide Charge

Protein phosphorylation is a key regulatory mechanism in eukaryotic cells. In the intrinsically disordered histone tails, phosphorylation is often a part of combinatorial post-translational modifications and an integral part of the “histone code” that regulates gene expression. Here, we study the association between two histone H3 tail peptides modified to different degrees, using fully atomistic molecular dynamics simulations. Assuming that the initial conformations are either α-helical or fully extended, we compare the propensity of the two peptides to associate with one another when both are unmodified, one modified and the other unmodified, or both modified. The simulations lead to the identification of distinct inter- and intramolecular interactions in the peptide dimer, highlighting a prominent role of a fine-tuned phosphorylation rheostat in peptide association. Progressive phosphorylation appears to modulate peptide charge, inducing strong and specific intermolecular interactions between the monomers, which do not result in the formation of amorphous or ordered aggregates, as documented by experimental evidence derived from Circular Dichroism and NMR spectroscopy. However, upon complete saturation of positive charges by phosphate groups, this effect is reversed: intramolecular interactions prevail and dimerization of zero-charge peptides is markedly reduced. These findings underscore the role of phosphorylation thresholds in the dynamics of intrinsically disordered proteins. Phosphorylation rheostats might account for the divergent effects of histone modifications on the modulation of chromatin structure.

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 Phosphorylation regulates the binding of intrinsically disordered proteins via a flexible conformation selection mechanism

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Na Liu ◽  
Yue Guo ◽  
Shangbo Ning ◽  
Mojie Duan
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Hydrophobic Interactions ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Regulation Mechanism ◽  
Enhanced Sampling ◽  
Dynamic Interactions ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Disordered Protein

Abstract Phosphorylation is one of the most common post-translational modifications. The phosphorylation of the kinase-inducible domain (KID), which is an intrinsically disordered protein (IDP), promotes the folding of KID and binding with the KID-interacting domain (KIX). However, the regulation mechanism of the phosphorylation on KID is still elusive. In this study, the structural ensembles and binding process of pKID and KIX are studied by all-atom enhanced sampling technologies. The results show that more hydrophobic interactions are formed in pKID, which promote the formation of the special hydrophobic residue cluster (HRC). The pre-formed HRC promotes binding to the correct sites of KIX and further lead the folding of pKID. Consequently, a flexible conformational selection model is proposed to describe the binding and folding process of intrinsically disordered proteins. The binding mechanism revealed in this work provides new insights into the dynamic interactions and phosphorylation regulation of proteins.

scholarly journals An intrinsically disordered proteins community for ELIXIR

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1753 ◽  
Author(s):  
Norman E. Davey ◽  
M. Madan Babu ◽  
Martin Blackledge ◽  
Alan Bridge ◽  
Salvador Capella-Gutierrez ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
White Paper ◽  
Disordered Proteins ◽  
Data Annotation ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Functional Characterisation ◽  
The Creation ◽  
University Of Padua

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are now recognised as major determinants in cellular regulation. This white paper presents a roadmap for future e-infrastructure developments in the field of IDP research within the ELIXIR framework. The goal of these developments is to drive the creation of high-quality tools and resources to support the identification, analysis and functional characterisation of IDPs. The roadmap is the result of a workshop titled “An intrinsically disordered protein user community proposal for ELIXIR” held at the University of Padua. The workshop, and further consultation with the members of the wider IDP community, identified the key priority areas for the roadmap including the development of standards for data annotation, storage and dissemination; integration of IDP data into the ELIXIR Core Data Resources; and the creation of benchmarking criteria for IDP-related software. Here, we discuss these areas of priority, how they can be implemented in cooperation with the ELIXIR platforms, and their connections to existing ELIXIR Communities and international consortia. The article provides a preliminary blueprint for an IDP Community in ELIXIR and is an appeal to identify and involve new stakeholders.

GRAS proteins: the versatile roles of intrinsically disordered proteins in plant signalling

2012 ◽  
Vol 442 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Xiaolin Sun ◽  
William T. Jones ◽  
Erik H. A. Rikkerink
Keyword(s):  
Plant Development ◽  
Intrinsically Disordered Proteins ◽  
Cell Signalling ◽  
Disordered Proteins ◽  
Cellular Functions ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteomes ◽  
Binding Interfaces ◽  
Molecular Recognition Features ◽  
Functional Versatility

IDPs (intrinsically disordered proteins) are highly abundant in eukaryotic proteomes and important for cellular functions, especially in cell signalling and transcriptional regulation. An IDR (intrinsically disordered region) within an IDP often undergoes disorder-to-order transitions upon binding to various partners, allowing an IDP to recognize and bind different partners at various binding interfaces. Plant-specific GRAS proteins play critical and diverse roles in plant development and signalling, and act as integrators of signals from multiple plant growth regulatory and environmental inputs. Possessing an intrinsically disordered N-terminal domain, the GRAS proteins constitute the first functionally required unfoldome from the plant kingdom. Furthermore, the N-terminal domains of GRAS proteins contain MoRFs (molecular recognition features), short interaction-prone segments that are located within IDRs and are able to recognize their interacting partners by undergoing disorder-to-order transitions upon binding to these specific partners. These MoRFs represent potential protein–protein binding sites and may be acting as molecular bait in recognition events during plant development. Intrinsic disorder provides GRAS proteins with a degree of binding plasticity that may be linked to their functional versatility. As an overview of structure–function relationships for GRAS proteins, the present review covers the main biological functions of the GRAS family, the IDRs within these proteins and their implications for understanding mode-of-action.

scholarly journals Protein Plasticity and its Role in Cellular Functions

2020 ◽  
Author(s):  
Sidra Ilyas ◽  
Abdul Manan
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Redox Homeostasis ◽  
Redox Status ◽  
Disordered Proteins ◽  
Redox Activity ◽  
Cellular Functions ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

ABSTRACTThe contribution of redox active properties of cysteines in intrinsically disordered regions (IDRs) of proteins is not very well acknowledged. Despite of providing structural stability and rigidity, intrinsically disordered cysteines are exceptional redox sensors and the redox status of the protein defines its structure. Experimental evidence suggests that the conformational heterogeneity of cysteines in intrinsically disordered proteins (IDPs) is related to numerous functions including regulation, structural changes and fuzzy complex formation. The unusual plasticity of IDPs make them suitable candidate to interact with many clients under specific conditions. Binding capabilities, dimerization and folding or unfolding nature of IDPs upon interaction with multiple clients assign distinct conformational changes associated with disulfide formation. Here we are going to focus on redox activity of IDPs, their dramatic roles that are not only restricted to cellular redox homeostasis and signaling pathways but also provide antioxidant, anti-apoptotic, binding and interactive power.

scholarly journals Sequence fingerprints distinguish erroneous from correct predictions of Intrinsically Disordered Protein Regions

2017 ◽  
Author(s):  
Konda Mani Saravanan ◽  
A Keith Dunker ◽  
Sankaran Krishnaswamy
Keyword(s):  
Amino Acid ◽  
False Positive ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Prediction Algorithm ◽  
Amino Acid Residues ◽  
Intrinsically Disordered ◽  
Distinguishing Features

ABSTRACTMore than sixty prediction methods for intrinsically disordered proteins (IDPs) have been developed over the years, many of which are accessible on the world-wide web. Nearly, all of these predictors give balanced accuracies in the ~65% to ~80% range. Since predictors are not perfect, further studies are required to uncover the role of amino acid residues in native IDP as compared to predicted IDP regions. In the present work, we make use of sequences of 100% predicted IDP regions, false positive disorder predictions, and experimentally determined IDP regions to distinguish the characteristics of native versus predicted IDP regions. A higher occurrence of asparagine is observed in sequences of native IDP regions but not in sequences of false positive predictions of IDP regions. The occurrences of certain combinations of amino acids at the pentapeptide level provide a distinguishing feature in the IDPs with respect to globular proteins. The distinguishing features presented in this paper provide insights into the sequence fingerprints of amino acid residues in experimentally-determined as compared to predicted IDP regions. These observations and additional work along these lines should enable the development of improvements in the accuracy of disorder prediction algorithm.

scholarly journals Connecting the αα-hubs: same fold, disordered ligands, new functions

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lasse Staby ◽  
Katrine Bugge ◽  
Rasmus Greve Falbe-Hansen ◽  
Edoardo Salladini ◽  
Karen Skriver ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Telomere Elongation ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Functional Understanding ◽  
Signal Specificity ◽  
Telomere Regulation ◽  
Secondary Structure Motif

Abstract Background Signal fidelity depends on protein–protein interaction–‘hubs’ integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the αα-hubs were defined, which are small α-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators. Methods Comparative structural biology. Results We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the αα-hubs. The new member of the αα-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the αα-hubs. As a common trait, the αα-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk. Conclusion The inclusion of the HHD in the αα-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the αα-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks.

MyelStones: the executive roles of myelin basic protein in myelin assembly and destabilization in multiple sclerosis

2015 ◽  
Vol 472 (1) ◽  
pp. 17-32 ◽  
Author(s):  
Kenrick A. Vassall ◽  
Vladimir V. Bamm ◽  
George Harauz
Keyword(s):  
Multiple Sclerosis ◽  
Myelin Basic Protein ◽  
Intrinsically Disordered Proteins ◽  
Basic Protein ◽  
Disordered Proteins ◽  
Post Translational Modifications ◽  
Src Homology 3 ◽  
Intrinsically Disordered ◽  
Src Homology ◽  
Membrane Anchoring

The classic isoforms of myelin basic protein (MBP, 14–21.5 kDa) are essential to formation of the multilamellar myelin sheath of the mammalian central nervous system (CNS). The predominant 18.5-kDa isoform links together the cytosolic surfaces of oligodendrocytes, but additionally participates in cytoskeletal turnover and membrane extension, Fyn-mediated signalling pathways, sequestration of phosphoinositides and maintenance of calcium homoeostasis. All MBP isoforms are intrinsically disordered proteins (IDPs) that interact via molecular recognition fragments (MoRFs), which thereby undergo local disorder-to-order transitions. Their conformations and associations are modulated by environment and by a dynamic barcode of post-translational modifications, particularly phosphorylation by mitogen-activated and other protein kinases and deimination [a hallmark of demyelination in multiple sclerosis (MS)]. The MBPs are thus to myelin what basic histones are to chromatin. Originally thought to be merely structural proteins forming an inert spool, histones are now known to be dynamic entities involved in epigenetic regulation and diseases such as cancer. Analogously, the MBPs are not mere adhesives of compact myelin, but active participants in oligodendrocyte proliferation and in membrane process extension and stabilization during myelinogenesis. A central segment of these proteins is pivotal in membrane-anchoring and SH3 domain (Src homology 3) interaction. We discuss in the present review advances in our understanding of conformational conversions of this classic basic protein upon membrane association, including new thermodynamic analyses of transitions into different structural ensembles and how a shift in the pattern of its post-translational modifications is associated with the pathogenesis and potentially onset of demyelination in MS.

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