scholarly journals Tubulin tails and their modifications regulate protein diffusion on microtubules

2020 ◽  
Vol 117 (16) ◽  
pp. 8876-8883 ◽  
Author(s):  
Lavi S. Bigman ◽  
Yaakov Levy
Keyword(s):  
Molecular Mechanism ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Coarse Grained ◽  
Protein Diffusion ◽  
Intrinsically Disordered ◽  
Essential Components ◽  
Regulate Protein ◽  
Dynamics Simulations

Microtubules (MTs) are essential components of the eukaryotic cytoskeleton that serve as “highways” for intracellular trafficking. In addition to the well-known active transport of cargo by motor proteins, many MT-binding proteins seem to adopt diffusional motility as a transportation mechanism. However, because of the limited spatial resolution of current experimental techniques, the detailed mechanism of protein diffusion has not been elucidated. In particular, the precise role of tubulin tails and tail modifications in the diffusion process is unclear. Here, using coarse-grained molecular dynamics simulations validated against atomistic simulations, we explore the molecular mechanism of protein diffusion along MTs. We found that electrostatic interactions play a central role in protein diffusion; the disordered tubulin tails enhance affinity but slow down diffusion, and diffusion occurs in discrete steps. While diffusion along wild-type MT is performed in steps of dimeric tubulin, the removal of the tails results in a step of monomeric tubulin. We found that the energy barrier for diffusion is larger when diffusion on MTs is mediated primarily by the MT tails rather than the MT body. In addition, globular proteins (EB1 and PRC1) diffuse more slowly than an intrinsically disordered protein (Tau) on MTs. Finally, we found that polyglutamylation and polyglycylation of tubulin tails lead to slower protein diffusion along MTs, although polyglycylation leads to faster diffusion across MT protofilaments. Taken together, our results explain experimentally observed data and shed light on the roles played by disordered tubulin tails and tail modifications in the molecular mechanism of protein diffusion along MTs.

The key role of electrostatic interactions in the induced folding in RNA recognition by DCL1-A

2018 ◽  
Vol 20 (14) ◽  
pp. 9376-9388 ◽  
Author(s):  
Lingci Zhao ◽  
Irina P. Suarez ◽  
Diego F. Gauto ◽  
Rodolfo M. Rasia ◽  
Jin Wang
Keyword(s):  
Molecular Mechanism ◽  
Electrostatic Interactions ◽  
Coarse Grained ◽  
Rna Recognition ◽  
Intrinsically Disordered ◽  
Induced Folding

We studied the molecular mechanism of the recognition of RNA by the intrinsically disordered DCL1-A with a coarse-grained structure-based model.

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>

scholarly journals Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics

Biomolecules ◽  
2012 ◽  
Vol 2 (1) ◽  
pp. 104-121 ◽  
Author(s):  
Koji Umezawa ◽  
Jinzen Ikebe ◽  
Mitsunori Takano ◽  
Haruki Nakamura ◽  
Junichi Higo
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Site ◽  
Complex Structure ◽  
Intrinsically Disordered Protein ◽  
Bound State ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Dynamics Simulations ◽  
High Flexibility

The phosphorylated kinase-inducible activation domain (pKID) adopts a helix–loop–helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and αB. We performed all-atom multicanonical molecular dynamics simulations of pKID with and without KIX in explicit solvents to generate conformational ensembles. Although the unbound pKID was disordered overall, αA and αB exhibited a nascent helix propensity; the propensity of αA was stronger than that of αB, which agrees with experimental results. In the bound state, the free-energy landscape of αB involved two low free-energy fractions: native-like and non-native fractions. This result suggests that αB folds according to the induced-fit mechanism. The αB-helix direction was well aligned as in the NMR complex structure, although the αA helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the αB helix can bind to another site of KIX, to which another protein MLL also binds with the adopting helix. Consequently, MLL can facilitate pKID binding to the pKID-binding site by blocking the MLL-binding site. This also supports experimentally obtained results.

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.

scholarly journals Anomalous Salt Dependence Reveals an Interplay of Attractive and Repulsive Electrostatic Interactions in α-synuclein Fibril Formation

QRB Discovery ◽  
2020 ◽  
Vol 1 ◽  
Author(s):  
Ricardo Gaspar ◽  
Mikael Lund ◽  
Emma Sparr ◽  
Sara Linse
Keyword(s):  
Ionic Strength ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Lipid Vesicles ◽  
Intrinsically Disordered ◽  
Catalytic Surfaces ◽  
Disordered Protein ◽  
Salt Dependence ◽  
Fluorescence Measurements ◽  
The One

Abstractα-Synuclein (α-syn) is an intrinsically disordered protein with a highly asymmetric charge distribution, whose aggregation is linked to Parkinson’s disease. The effect of ionic strength was investigated at mildly acidic pH (5.5) in the presence of catalytic surfaces in the form of α-syn seeds or anionic lipid vesicles using thioflavin T fluorescence measurements. Similar trends were observed with both surfaces: increasing ionic strength reduced the rate of α-syn aggregation although the surfaces as well as α-syn have a net negative charge at pH 5.5. This anomalous salt dependence implies that short-range attractive electrostatic interactions are critical for secondary nucleation as well as heterogeneous primary nucleation. Such interactions were confirmed in Monte Carlo simulations of α-syn monomers interacting with surface-grafted C-terminal tails, and found to be weakened in the presence of salt. Thus, nucleation of α-syn aggregation depends critically on an attractive electrostatic component that is screened by salt to the extent that it outweighs the screening of the long-range repulsion between negatively charged monomers and negative surfaces. Interactions between the positively charged N-termini of α-syn monomers on the one hand, and the negatively C-termini of α-syn on fibrils or vesicles surfaces on the other hand, are thus critical for nucleation.

scholarly journals Modelling lipid systems in fluid with Lattice Boltzmann Molecular Dynamics simulations and hydrodynamics

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Astrid F. Brandner ◽  
Stepan Timr ◽  
Simone Melchionna ◽  
Philippe Derreumaux ◽  
Marc Baaden ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Lattice Boltzmann ◽  
Coarse Grained ◽  
Implicit Solvent ◽  
Mesoscopic Scale ◽  
Coarse Grained Model ◽  
Dynamics Simulations ◽  
Cellular Compartments ◽  
Biological Entities

Abstract In this work we present the coupling between Dry Martini, an efficient implicit solvent coarse-grained model for lipids, and the Lattice Boltzmann Molecular Dynamics (LBMD) simulation technique in order to include naturally hydrodynamic interactions in implicit solvent simulations of lipid systems. After validating the implementation of the model, we explored several systems where the action of a perturbing fluid plays an important role. Namely, we investigated the role of an external shear flow on the dynamics of a vesicle, the dynamics of substrate release under shear, and inquired the dynamics of proteins and substrates confined inside the core of a vesicle. Our methodology enables future exploration of a large variety of biological entities and processes involving lipid systems at the mesoscopic scale where hydrodynamics plays an essential role, e.g. by modulating the migration of proteins in the proximity of membranes, the dynamics of vesicle-based drug delivery systems, or, more generally, the behaviour of proteins in cellular compartments.

scholarly journals Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 337 ◽  
Author(s):  
Hognon ◽  
Gebus ◽  
Barone ◽  
Monari
Keyword(s):  
Electrostatic Interactions ◽  
Empty Site ◽  
Quadruplex Structure ◽  
Abasic Sites ◽  
Human Dna ◽  
Guanine Quadruplex ◽  
Guanine Base ◽  
The Stability ◽  
Dynamics Simulations

By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.

Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation

Science ◽  
2019 ◽  
Vol 365 (6455) ◽  
pp. 825-829 ◽  
Author(s):  
Tae Hun Kim ◽  
Brian Tsang ◽  
Robert M. Vernon ◽  
Nahum Sonenberg ◽  
Lewis E. Kay ◽  
...  
Keyword(s):  
Phase Separation ◽  
Rna Processing ◽  
Intrinsically Disordered Protein ◽  
Resonance Spectroscopy ◽  
Specific Interactions ◽  
Intrinsically Disordered ◽  
Functional Consequences ◽  
Translational Regulators

Membraneless organelles involved in RNA processing are biomolecular condensates assembled by phase separation. Despite the important role of intrinsically disordered protein regions (IDRs), the specific interactions underlying IDR phase separation and its functional consequences remain elusive. To address these questions, we used minimal condensates formed from the C-terminal disordered regions of two interacting translational regulators, FMRP and CAPRIN1. Nuclear magnetic resonance spectroscopy of FMRP-CAPRIN1 condensates revealed interactions involving arginine-rich and aromatic-rich regions. We found that different FMRP serine/threonine and CAPRIN1 tyrosine phosphorylation patterns control phase separation propensity with RNA, including subcompartmentalization, and tune deadenylation and translation rates in vitro. The resulting evidence for residue-specific interactions underlying co–phase separation, phosphorylation-modulated condensate architecture, and enzymatic activity within condensates has implications for how the integration of signaling pathways controls RNA processing and translation.

Molecular dynamics simulations of the intrinsically disordered protein amelogenin

2016 ◽  
Vol 35 (8) ◽  
pp. 1813-1823 ◽  
Author(s):  
Alessandra Apicella ◽  
Matteo Marascio ◽  
Vincenzo Colangelo ◽  
Monica Soncini ◽  
Alfonso Gautieri ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Intrinsically Disordered Protein ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Dynamics Simulations

scholarly journals Histidine-rich Ca2+-binding protein stimulates the transport cycle of SERCA through a conformation-dependent fuzzy complex

2020 ◽  
Author(s):  
Temitope I. Ayeotan ◽  
Line Cecilie Hansen ◽  
Thomas Boesen ◽  
Claus Olesen ◽  
Jesper V. Møller ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Binding Protein ◽  
Intrinsically Disordered Protein ◽  
Bound State ◽  
Disordered Proteins ◽  
Dependent Manner ◽  
Intrinsically Disordered ◽  
Intracellular Ca ◽  
P Type ◽  
Rate Limiting

AbstractThe histidine-rich Ca2+-binding protein (HRC) stimulates the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) to increase Ca2+-uptake into the lumen. HRC also binds the triadin scaffold in a Ca2+-dependent manner, and HRC tunes both the uptake and release of Ca2+ depending on the concentration in the intracellular Ca2+-stores. We investigated how HRC stimulates SERCA pumping using biochemical and biophysical assays, and show that HRC is an intrinsically disordered protein that binds directly to SERCA via electrostatic interactions. The affinity of the interaction depends on the conformation of SERCA, and HRC binds most tightly in the calcium-released E2P state. This state marks the end of the rate-limiting [Ca2]E1P to E2P transition of SERCA, and suggests that HRC stimulates SERCA by preferentially stabilizing the end point of this transition. HRC remains disordered in the bound state and thus binds in a dynamic, fuzzy complex. The binding of HRC to SERCA shows that fuzzy complexes formed by disordered proteins may be conformation-specific, and use this specificity to modulate the functional cycle of complex molecular machines such as a P-type ATPase.

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