scholarly journals Investigation into Early Steps of Actin Recognition by the Intrinsically Disordered N-WASP Domain V

2019 ◽  
Vol 20 (18) ◽  
pp. 4493 ◽  
Author(s):  
Maud Chan-Yao-Chong ◽  
Dominique Durand ◽  
Tâp Ha-Duong
Keyword(s):  
Conformational Changes ◽  
Actin Polymerization ◽  
High Specificity ◽  
Physical Factors ◽  
Consensus Sequences ◽  
Recognition Process ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Dynamics Simulations ◽  
Domain V

Cellular regulation or signaling processes are mediated by many proteins which often have one or several intrinsically disordered regions (IDRs). These IDRs generally serve as binders to different proteins with high specificity. In many cases, IDRs undergo a disorder-to-order transition upon binding, following a mechanism between two possible pathways, the induced fit or the conformational selection. Since these mechanisms contribute differently to the kinetics of IDR associations, it is important to investigate them in order to gain insight into the physical factors that determine the biomolecular recognition process. The verprolin homology domain (V) of the Neural Wiskott–Aldrich Syndrome Protein (N-WASP), involved in the regulation of actin polymerization, is a typical example of IDR. It is composed of two WH2 motifs, each being able to bind one actin molecule. In this study, we investigated the early steps of the recognition process of actin by the WH2 motifs of N-WASP domain V. Using docking calculations and molecular dynamics simulations, our study shows that actin is first recognized by the N-WASP domain V regions which have the highest propensity to form transient α -helices. The WH2 motif consensus sequences “LKKV” subsequently bind to actin through large conformational changes of the disordered domain V.

scholarly journals Optimization of Molecular Dynamics Simulations of c-MYC1-88—An Intrinsically Disordered System

Life ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 109 ◽  
Author(s):  
Sandra S. Sullivan ◽  
Robert O.J. Weinzierl
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Proliferation And Apoptosis ◽  
Conventional Structure ◽  
Experimental Approaches ◽  
Dynamics Simulations

Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the primary sequence is disordered. Computational approaches that shed light on the range of secondary and tertiary structural conformations therefore provide the only realistic chance to study such proteins. Here, we describe the results of several tests of force fields and water models employed in molecular dynamics simulations for the N-terminal 88 amino acids of c-MYC. Comparisons of the simulation data with experimental secondary structure assignments obtained by NMR establish a particular implicit solvation approach as highly congruent. The results provide insights into the structural dynamics of c-MYC1-88, which will be useful for guiding future experimental approaches. The protocols for trajectory analysis described here will be applicable for the analysis of a variety of computational simulations of intrinsically disordered proteins.

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 Defining binding motifs and dynamics of the multi-pocket FERM domain from ezrin, radixin, moesin and merlin

2020 ◽  
Author(s):  
Muhammad Ali ◽  
Alisa Khramushin ◽  
Vikash K Yadav ◽  
Ora Schueler-Furman ◽  
Ylva Ivarsson
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Cell Cortex ◽  
List Type ◽  
Binding Assays ◽  
Ferm Domain ◽  
Binding Motifs ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

AbstractThe ERMs (ezrin, radixin and moesin) and the closely related merlin (NF2) participate in signaling events at the cell cortex through interactions mediated by their conserved FERM domain. We systematically investigated the FERM domain mediated interactions with short linear motifs (SLiMs) by screening the FERM domains againsts a phage peptidome representing intrinsically disordered regions of the human proteome. We uncovered a diverse set of interacting partners with similar but distinct binding motifs (FYDF, xYxV, FY(D/E)L and LQE(I/L) that bind to distinct binding pockets. We validated interactions between moesin and merlin FERM domains and full-length FAM83G, HIF1A, LATS1, NOP53, PAK6, RRBP1 and ZNF622 through pull-down experiments. Using biophysical binding assays, we determined affinities of, and uncovered allosteric interdependencies between, different binding partners, suggesting that the FERM domain acts as a switchable interaction hub. Using Rosetta FlexPepDock computational peptide docking protocols, we investigated the energy landscapes of identified interactions, which provide a detailed molecular understanding of the binding of the distinct binding motifs, as well as possible allosteric interconnections. This study demonstrates how experimental and computational approaches together can unravel a complex system of protein-peptide interactions that includes a family of proteins with multiple binding sites that interact with similar but distinct binding motifs.HighlightsWe screened the human disorderome for motif-containing partners of the FERM domainsWe expand the ERM and merlin interactomes of the ERMs and merlinWe identify four distinct motif classes that bind the ERM and merlin FERM domains: FYDF, xYxV, FY(D/E)L and LQE(I/L)In-vitro and in-silico data suggest that the FYDF motif binds to the F3a site and that xYxV motif binds to the F3b siteIn-silico modelling sheds light on the underlying conformational changes responsible for ligand interdependenciesAbstract Figure

scholarly journals Extreme Fuzzy Association of an Intrinsically Disordered Protein with Acidic Membranes

2020 ◽  
Author(s):  
Alan Hicks ◽  
Cristian A. Escobar ◽  
Timothy A. Cross ◽  
Huan-Xiang Zhou
Keyword(s):  
Molecular Dynamics ◽  
Solid State Nmr ◽  
Transmembrane Helix ◽  
Intrinsically Disordered Protein ◽  
Membrane Association ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Membrane Tethering ◽  
Dynamics Simulations

AbstractMany physiological and pathophysiological processes, including Mycobacterium tuberculosis (Mtb) cell division, may involve fuzzy membrane association by proteins via intrinsically disordered regions. The fuzziness is extreme when the conformation and pose of the bound protein and the composition of the proximal lipids are all highly dynamic. Here we tackled the challenge in characterizing the extreme fuzzy membrane association of the disordered, cytoplasmic N-terminal region (NT) of ChiZ, an Mtb divisome protein, by combining solution and solid-state NMR spectroscopy and molecular dynamics simulations. In a typical pose, NT is anchored to acidic membranes by Arg residues in the midsection. Competition for Arg interactions between lipids and acidic residues, all in the first half of NT, makes the second half more prominent in membrane association. This asymmetry is accentuated by membrane tethering of the downstream transmembrane helix. These insights into sequence-interaction relations may serve as a paradigm for understanding fuzzy membrane association.

scholarly journals Polarisome assembly mediates actin remodeling during polarized yeast and fungal growth

2021 ◽  
Vol 134 (1) ◽  
pp. jcs247916
Author(s):  
Ying Xie ◽  
Yansong Miao
Keyword(s):  
Actin Polymerization ◽  
Budding Yeast ◽  
Fungal Growth ◽  
System Response ◽  
Macromolecular Complex ◽  
Cell Axis ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Dynamic Assembly ◽  
Actin Cables

ABSTRACTDynamic assembly and remodeling of actin is critical for many cellular processes during development and stress adaptation. In filamentous fungi and budding yeast, actin cables align in a polarized manner along the mother-to-daughter cell axis, and are essential for the establishment and maintenance of polarity; moreover, they rapidly remodel in response to environmental cues to achieve an optimal system response. A formin at the tip region within a macromolecular complex, called the polarisome, is responsible for driving actin cable polymerization during polarity establishment. This polarisome undergoes dynamic assembly through spatial and temporally regulated interactions between its components. Understanding this process is important to comprehend the tuneable activities of the formin-centered nucleation core, which are regulated through divergent molecular interactions and assembly modes within the polarisome. In this Review, we focus on how intrinsically disordered regions (IDRs) orchestrate the condensation of the polarisome components and the dynamic assembly of the complex. In addition, we address how these components are dynamically distributed in and out of the assembly zone, thereby regulating polarized growth. We also discuss the potential mechanical feedback mechanisms by which the force-induced actin polymerization at the tip of the budding yeast regulates the assembly and function of the polarisome.

scholarly journals Energetics of a protein disorder-order transition in small molecule recognition

2021 ◽  
Author(s):  
Cesar Mendoza-Martinez ◽  
Michail Papadourakis ◽  
salome llabres ◽  
Arun A Gupta ◽  
Paul N Barlow ◽  
...  
Keyword(s):  
Small Molecule ◽  
Order Transition ◽  
Protein Disorder ◽  
Enhanced Sampling ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Binding Energetics ◽  
Molecule Recognition ◽  
Dynamics Simulations ◽  
Disordered Regions

Many proteins recognise other proteins via mechanisms that involve the folding of intrinsically disordered regions upon complex formation. Here we investigate how the selectivity of a drug-like small molecule arises from its modulation of a protein disorder-to-order transition. Binding of the compound AM-7209 has been reported to confer order upon an intrinsically disordered lid region of the oncoprotein MDM2. Calorimetric measurements revealed that truncation of the lid region of MDM2 increases the dissociation constant of AM-7209 250-fold. By contrast, lid truncation has little effect on the binding of the ligand Nutlin-3a. Insights into these differential binding energetics were obtained via a complete thermodynamic analysis that featured adaptive absolute alchemical free energy of binding calculations with enhanced-sampling molecular dynamics simulations. The simulations reveal that in apo MDM2 the ordered lid state is energetically disfavoured. AM-7209, but not Nutlin-3a, shows a significant energetic preference for ordered lid conformations, thus shifting the balance towards ordering of the lid in the AM-7209/MDM2 complex. The methodology reported herein should facilitate broader targeting of intrinsically disordered regions in medicinal chemistry.

scholarly journals Ubiquitin Interacting Motifs: Duality Between Structured and Disordered Motifs

2021 ◽  
Vol 8 ◽  
Author(s):  
Matteo Lambrughi ◽  
Emiliano Maiani ◽  
Burcu Aykac Fas ◽  
Gary S. Shaw ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Protein Function ◽  
Chemical Shifts ◽  
Helical Structures ◽  
Conserved Sequence ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Multiple Partners ◽  
Common Motif ◽  
Dynamics Simulations ◽  
Disordered Regions

Ubiquitin is a small protein at the heart of many cellular processes, and several different protein domains are known to recognize and bind ubiquitin. A common motif for interaction with ubiquitin is the Ubiquitin Interacting Motif (UIM), characterized by a conserved sequence signature and often found in multi-domain proteins. Multi-domain proteins with intrinsically disordered regions mediate interactions with multiple partners, orchestrating diverse pathways. Short linear motifs for binding are often embedded in these disordered regions and play crucial roles in modulating protein function. In this work, we investigated the structural propensities of UIMs using molecular dynamics simulations and NMR chemical shifts. Despite the structural portrait depicted by X-crystallography of stable helical structures, we show that UIMs feature both helical and intrinsically disordered conformations. Our results shed light on a new class of disordered UIMs. This group is here exemplified by the C-terminal domain of one isoform of ataxin-3 and a group of ubiquitin-specific proteases. Intriguingly, UIMs not only bind ubiquitin. They can be a recruitment point for other interactors, such as parkin and the heat shock protein Hsc70-4. Disordered UIMs can provide versatility and new functions to the client proteins, opening new directions for research on their interactome.

scholarly journals Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

2021 ◽  
Vol 22 (11) ◽  
pp. 6016
Author(s):  
Niccolò Candelise ◽  
Silvia Scaricamazza ◽  
Illari Salvatori ◽  
Alberto Ferri ◽  
Cristiana Valle ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Clinical Relevance ◽  
Phenotypic Diversity ◽  
Intrinsically Disordered Protein ◽  
Structural Heterogeneity ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Β Sheet

Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

Long-Range Entropic Effects on Protein Intrinsically Disordered Regions

2019 ◽  
Author(s):  
Joao Victor de Souza Cunha ◽  
Agnieszka K. Bronowska
Keyword(s):  
Conformational Changes ◽  
Binding Free Energy ◽  
Configurational Entropy ◽  
Grand Challenge ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Protein Conformational Changes ◽  
Structural Entropy ◽  
Novel Method ◽  
Entropic Effects

Entropy calculations represent one of the most challenging steps in obtaining the binding free energy in proteins and their complexes, which is a grand challenge in computational biology. In this paper we define the workframe of a novel method to calculate structural entropy for protein molecular simulation : SQuE ( Strucutral Quantifier of Entropy). Using a first degree approximation for the probability distribution, we were able to calculate the entropic effects that emerges from a intrinsically disordered (ID) region in UDP-glucose 6-dehydrogenase (UGDH) protein structure. We were able to quantify the configurational entropy difference in the structured core caused by the truncation of the C-terminal ID-tail, and evaluate the protein conformational changes in the structured domain.<br>

scholarly journals Intrinsically disordered proteins: controlled chaos or random walk

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
T.C. Howton ◽  
Yingqian Ada Zhan ◽  
Yali Sun ◽  
M. Shahid Mukhtar
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Conformational Dynamics ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Specific Proteins ◽  
Free Energy Landscapes ◽  
Dynamics Simulations ◽  
Fixed Structure

Traditional conventions that a protein’s sequence dictates its definitive, tertiary structure, and that this fixed structure provides the protein with the ability to carry out its designated role(s) are still correct but not for all proteins. Research over the past decade discovered that several key proteins possess intrinsically disordered regions (IDRs) that are crucial to their ability to perform specific functions and are observed clustered together within important classes of proteins. In this review, we aim to demonstrate how free energy landscapes, molecular dynamics simulations, and homology modeling are helpful in understanding key conformational dynamics of intrinsically disordered proteins (IDPs). Additionally, we use a list of predicted IDPs found in Arabidopsis to identify chromatin organizers and transcriptional regulators as being highly enriched in IDPs. Furthermore, we focus our attention to specific proteins within these families such as HAC5, EFS, ANAC019, ANAC013, and ANAC046. Future studies are needed to experimentally identify additional IDPs and their binding mechanisms.

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