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.

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.

scholarly journals Co-Evolution of Intrinsically Disordered Proteins with Folded Partners Witnessed by Evolutionary Couplings

2018 ◽  
Vol 19 (11) ◽  
pp. 3315 ◽  
Author(s):  
Rita Pancsa ◽  
Fruzsina Zsolyomi ◽  
Peter Tompa
Keyword(s):  
Large Scale ◽  
Intrinsically Disordered Proteins ◽  
Protein Structures ◽  
Disordered Proteins ◽  
Cellular Interaction ◽  
Structural Constraints ◽  
Protein Residues ◽  
Intrinsically Disordered ◽  
Evolutionary Changes ◽  
Folded Proteins

Although improved strategies for the detection and analysis of evolutionary couplings (ECs) between protein residues already enable the prediction of protein structures and interactions, they are mostly restricted to conserved and well-folded proteins. Whereas intrinsically disordered proteins (IDPs) are central to cellular interaction networks, due to the lack of strict structural constraints, they undergo faster evolutionary changes than folded domains. This makes the reliable identification and alignment of IDP homologs difficult, which led to IDPs being omitted in most large-scale residue co-variation analyses. By preforming a dedicated analysis of phylogenetically widespread bacterial IDP–partner interactions, here we demonstrate that partner binding imposes constraints on IDP sequences that manifest in detectable interprotein ECs. These ECs were not detected for interactions mediated by short motifs, rather for those with larger IDP–partner interfaces. Most identified coupled residue pairs reside close (<10 Å) to each other on the interface, with a third of them forming multiple direct atomic contacts. EC-carrying interfaces of IDPs are enriched in negatively charged residues, and the EC residues of both IDPs and partners preferentially reside in helices. Our analysis brings hope that IDP–partner interactions difficult to study could soon be successfully dissected through residue co-variation analysis.

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.

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 The impact of O-glycan chemistry on the stability of intrinsically disordered proteins

2018 ◽  
Vol 9 (15) ◽  
pp. 3710-3715 ◽  
Author(s):  
Erica T. Prates ◽  
Xiaoyang Guan ◽  
Yaohao Li ◽  
Xinfeng Wang ◽  
Patrick K. Chaffey ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Glycosylation ◽  
Disordered Proteins ◽  
Biological Functions ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
P Protein ◽  
The Stability ◽  
The Impact

Protein glycosylation is a diverse post-translational modification that serves myriad biological functions.

scholarly journals Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level

Biomolecules ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 77 ◽  
Author(s):  
Xingcheng Lin ◽  
Prakash Kulkarni ◽  
Federico Bocci ◽  
Nicholas Schafer ◽  
Susmita Roy ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Conformational Dynamics ◽  
Structural Plasticity ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Related Disorder ◽  
Structural Ordering ◽  
Intrinsically Disordered ◽  
Collective Motions ◽  
Folded Proteins

Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences.

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 Expanding the proteome: disordered and alternatively folded proteins

2011 ◽  
Vol 44 (4) ◽  
pp. 467-518 ◽  
Author(s):  
H. Jane Dyson
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Significant Proportion ◽  
Experimental Studies ◽  
Three Dimensional ◽  
Protein Sequences ◽  
Open Reading Frames ◽  
Disordered Proteins ◽  
Characteristic Functions ◽  
Intrinsically Disordered ◽  
Folded Proteins

AbstractProteins provide much of the scaffolding for life, as well as undertaking a variety of essential catalytic reactions. These characteristic functions have led us to presuppose that proteins are in general functional only when well structured and correctly folded. As we begin to explore the repertoire of possible protein sequences inherent in the human and other genomes, two stark facts that belie this supposition become clear: firstly, the number of apparent open reading frames in the human genome is significantly smaller than appears to be necessary to code for all of the diverse proteins in higher organisms, and secondly that a significant proportion of the protein sequences that would be coded by the genome would not be expected to form stable three-dimensional (3D) structures. Clearly the genome must include coding for a multitude of alternative forms of proteins, some of which may be partly or fully disordered or incompletely structured in their functional states. At the same time as this likelihood was recognized, experimental studies also began to uncover examples of important protein molecules and domains that were incompletely structured or completely disordered in solution, yet remained perfectly functional. In the ensuing years, we have seen an explosion of experimental and genome-annotation studies that have mapped the extent of the intrinsic disorder phenomenon and explored the possible biological rationales for its widespread occurrence. Answers to the question ‘why would a particular domain need to be unstructured?’ are as varied as the systems where such domains are found. This review provides a survey of recent new directions in this field, and includes an evaluation of the role not only of intrinsically disordered proteins but also of partially structured and highly dynamic members of the disorder–order continuum.

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