scholarly journals Interactions of noncanonical motifs with hnRNP A2 promote activity-dependent RNA transport in neurons

2014 ◽  
Vol 205 (4) ◽  
pp. 493-510 ◽  
Author(s):  
Ilham A. Muslimov ◽  
Aliya Tuzhilin ◽  
Thean Hock Tang ◽  
Robert K.S. Wong ◽  
Riccardo Bianchi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Targeted Delivery ◽  
Receptor Activation ◽  
Messenger Rnas ◽  
Rna Transport ◽  
Ribonucleic Acids ◽  
Rna Targeting ◽  
Rna Motif ◽  
Dendritic Rna ◽  
Activity Dependent

A key determinant of neuronal functionality and plasticity is the targeted delivery of select ribonucleic acids (RNAs) to synaptodendritic sites of protein synthesis. In this paper, we ask how dendritic RNA transport can be regulated in a manner that is informed by the cell’s activity status. We describe a molecular mechanism in which inducible interactions of noncanonical RNA motif structures with targeting factor heterogeneous nuclear ribonucleoprotein (hnRNP) A2 form the basis for activity-dependent dendritic RNA targeting. High-affinity interactions between hnRNP A2 and conditional GA-type RNA targeting motifs are critically dependent on elevated Ca2+ levels in a narrow concentration range. Dendritic transport of messenger RNAs that carry such GA motifs is inducible by influx of Ca2+ through voltage-dependent calcium channels upon β-adrenergic receptor activation. The combined data establish a functional correspondence between Ca2+-dependent RNA–protein interactions and activity-inducible RNA transport in dendrites. They also indicate a role of genomic retroposition in the phylogenetic development of RNA targeting competence.

scholarly journals Spatial code recognition in neuronal RNA targeting: Role of RNA–hnRNP A2 interactions

2011 ◽  
Vol 194 (3) ◽  
pp. 441-457 ◽  
Author(s):  
Ilham A. Muslimov ◽  
Mihir V. Patel ◽  
Arthur Rose ◽  
Henri Tiedge
Keyword(s):  
Translational Control ◽  
Targeted Delivery ◽  
Fragile X ◽  
Regulation Of Gene Expression ◽  
Rna Transport ◽  
Transport Pathway ◽  
Transport Pathways ◽  
Cgg Repeat ◽  
Rna Targeting ◽  
Nucleotide Interactions

In neurons, regulation of gene expression occurs in part through translational control at the synapse. A fundamental requirement for such local control is the targeted delivery of select neuronal mRNAs and regulatory RNAs to distal dendritic sites. The nature of spatial RNA destination codes, and the mechanism by which they are interpreted for dendritic delivery, remain poorly understood. We find here that in a key dendritic RNA transport pathway (exemplified by BC1 RNA, a dendritic regulatory RNA, and protein kinase M ζ [PKMζ] mRNA, a dendritic mRNA), noncanonical purine•purine nucleotide interactions are functional determinants of RNA targeting motifs. These motifs are specifically recognized by heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2), a trans-acting factor required for dendritic delivery. Binding to hnRNP A2 and ensuing dendritic delivery are effectively competed by RNAs with CGG triplet repeat expansions. CGG repeats, when expanded in the 5′ untranslated region of fragile X mental retardation 1 (FMR1) mRNA, cause fragile X–associated tremor/ataxia syndrome. The data suggest that cellular dysregulation observed in the presence of CGG repeat RNA may result from molecular competition in neuronal RNA transport pathways.

scholarly journals A Global Review on Short Peptides: Frontiers and Perspectives

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 430
Author(s):  
Vasso Apostolopoulos ◽  
Joanna Bojarska ◽  
Tsun-Thai Chai ◽  
Sherif Elnagdy ◽  
Krzysztof Kaczmarek ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Targeted Delivery ◽  
Swot Analysis ◽  
Functional Materials ◽  
Great Promise ◽  
Short Peptides ◽  
Altered Peptide Ligands ◽  
Short Peptide ◽  
Domains Of Life

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide “drugs” initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

scholarly journals Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 106
Author(s):  
Pavel V. Ershov ◽  
Yuri V. Mezentsev ◽  
Alexis S. Ivanov
Keyword(s):  
Protein Interactions ◽  
Targeted Delivery ◽  
Protein Complexes ◽  
Protein Protein Interactions ◽  
Good Efficiency ◽  
Cellular Targets ◽  
Proteolytic Stability ◽  
Clinically Significant

The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

scholarly journals Modulation of A2aR Oligomerisation by Conformational State and PIP2 Interactions Revealed by MD Simulations and Markov Models

2020 ◽  
Author(s):  
Wanling Song ◽  
Anna L. Duncan ◽  
Mark S.P. Sansom
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Markov Models ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Membrane Lipid ◽  
Intracellular Loop ◽  
Gpcr Activation ◽  
State Models

AbstractG protein-coupled receptors (GPCRs) play key roles in cellular signalling. GPCRs are suggested to form dimers and higher order oligomers in response to activation. However, we do not fully understand GPCR activation at larger scales and in an in vivo context. We have characterised oligomeric configurations of the adenosine 2a receptor (A2aR) by combining large-scale molecular dynamics simulations with Markov state models. Receptor activation results in enhanced oligomerisation, more diverse oligomer populations, and a more connected oligomerisation network. The active state conformation of the A2aR shifts protein-protein association interfaces to those involving intracellular loop ICL3 and transmembrane helix TM6. Binding of PIP2 to A2aR stabilises protein-protein interactions via PIP2-mediated association interfaces. These results indicate that A2aR oligomerisation is responsive to the local membrane lipid environment. This in turn suggests a modulatory effect on A2aR whereby a given oligomerisation profile favours the dynamic formation of specific supra-molecular signalling complexes.

Spike Patterning by Ca2+-Dependent Regulation of a Muscarinic Cation Current in Entorhinal Cortex Layer II Neurons

2004 ◽  
Vol 92 (3) ◽  
pp. 1644-1657 ◽  
Author(s):  
Jacopo Magistretti ◽  
Li Ma ◽  
Mark H. Shalinsky ◽  
Wei Lin ◽  
Ruby Klink ◽  
...  
Keyword(s):  
Entorhinal Cortex ◽  
Chelating Agents ◽  
Receptor Activation ◽  
Emergent Properties ◽  
Firing Activity ◽  
Cation Current ◽  
Muscarinic Stimulation ◽  
Intracellular Ca ◽  
Positive And Negative Feedback ◽  
Activity Dependent

In entorhinal cortex layer II neurons, muscarinic receptor activation promotes depolarization via activation of a nonspecific cation current ( INCM). Under muscarinic influence, these neurons also develop changes in excitability that result in activity-dependent induction of delayed firing and bursting activity. To identify the membrane processes underlying these phenomena, we examined whether INCM may undergo activity-dependent regulation. Our voltage-clamp experiments revealed that appropriate depolarizing protocols increased the basal level of inward current activated during muscarinic stimulation and suggested that this effect was due to INCM upregulation. In the presence of low buffering for intracellular Ca2+, this upregulation was transient, and its decay could be followed by a phase of INCM downregulation. Both up- and downregulation were elicited by depolarizing stimuli able to activate voltage-gated Ca2+ channels (VGCC); both were sensitive to increasing concentrations of intracellular Ca2+-chelating agents with downregulation being abolished at lower Ca2+-buffering capacities; both were reduced or suppressed by VGCC block or in the absence of extracellular Ca2+. These data indicate that relatively small increases in [Ca2+]i driven by firing activity can induce upregulation of a basal muscarinic depolarizing-current level, whereas more pronounced [Ca2+]i elevations can result in INCM downregulation. We propose that the interaction of activity-dependent positive and negative feedback mechanisms on INCM allows entorhinal cortex layer II neurons to exhibit emergent properties, such as delayed firing and enhanced or suppressed responses to repeated stimuli, that may be of importance in the memory functions of the temporal lobe and in the pathophysiology of epilepsy.

scholarly journals Pur .ALPHA. Protein Implicated in Dendritic RNA Transport Interacts with Ribosomes in Neuronal Cytoplasm.

2001 ◽  
Vol 24 (3) ◽  
pp. 231-235 ◽  
Author(s):  
Yanmei LI ◽  
Katsuya KOIKE ◽  
Sachiyo OHASHI ◽  
Tomoko FUNAKOSHI ◽  
Masahiro TADANO ◽  
...  
Keyword(s):  
Rna Transport ◽  
Dendritic Rna

scholarly journals MicroRNA-based therapeutics in cardiovascular disease: screening and delivery to the target

2017 ◽  
Vol 46 (1) ◽  
pp. 11-21 ◽  
Author(s):  
David Mellis ◽  
Andrea Caporali
Keyword(s):  
Targeted Delivery ◽  
Transcriptional Regulators ◽  
Messenger Rnas ◽  
Biological Responses ◽  
Cardiovascular Biology ◽  
Non Coding Rnas ◽  
Novel Approaches ◽  
Cardiovascular Cells ◽  
Mirna Therapeutics ◽  
Mirna Targeting

MicroRNAs (miRNAs) are small non-coding RNAs of ∼22 nucleotides, which have increasingly been recognized as potent post-transcriptional regulators of gene expression. MiRNA targeting is defined by the complementarities between positions 2–8 of miRNA 5′-end with generally the 3′-untranslated region of target mRNAs (messenger RNAs). The capacity of miRNAs to simultaneously inhibit many different mRNAs allows for an amplification of biological responses. Hence, miRNAs are extremely attractive targets for therapeutic regulation in several diseases, including cardiovascular. Novel approaches are emerging to identify the miRNA functions in cardiovascular biology processes and to improve miRNA delivery in the heart and vasculature. In the present study, we provide an overview of current studies of miRNA functions in cardiovascular cells by the use of high-content screening. We also discuss the challenge to achieve a safe and targeted delivery of miRNA therapeutics in cardiovascular cells.

scholarly journals Notch ligand activity is modulated by glycosphingolipid membrane composition in Drosophila melanogaster

2010 ◽  
Vol 188 (4) ◽  
pp. 581-594 ◽  
Author(s):  
Sophie Hamel ◽  
Jacques Fantini ◽  
François Schweisguth
Keyword(s):  
Protein Interactions ◽  
Receptor Activation ◽  
Notch Receptor ◽  
Binding Motif ◽  
Membrane Composition ◽  
Notch Receptors ◽  
Notch Ligands ◽  
Ligand Activity ◽  
Signaling Activity

Endocytosis of the transmembrane ligands Delta (Dl) and Serrate (Ser) is required for the proper activation of Notch receptors. The E3 ubiquitin ligases Mindbomb1 (Mib1) and Neuralized (Neur) regulate the ubiquitination of Dl and Ser and thereby promote both ligand endocytosis and Notch receptor activation. In this study, we identify the α1,4-N-acetylgalactosaminyltransferase-1 (α4GT1) gene as a gain of function suppressor of Mib1 inhibition. Expression of α4GT1 suppressed the signaling and endocytosis defects of Dl and Ser resulting from the inhibition of mib1 and/or neur activity. Genetic and biochemical evidence indicate that α4GT1 plays a regulatory but nonessential function in Notch signaling via the synthesis of a specific glycosphingolipid (GSL), N5, produced by α4GT1. Furthermore, we show that the extracellular domain of Ser interacts with GSLs in vitro via a conserved GSL-binding motif, raising the possibility that direct GSL–protein interactions modulate the endocytosis of Notch ligands. Together, our data indicate that specific GSLs modulate the signaling activity of Notch ligands.

scholarly journals Lipid-mediated Association of the Slg1 Transmembrane Domains in Yeast Plasma Membranes

2021 ◽  
Author(s):  
Azadeh Alavizargar ◽  
Annegret Eltig ◽  
Roland Wedlich Soeldner ◽  
Andreas Heuer
Keyword(s):  
Plasma Membrane ◽  
Protein Interactions ◽  
Plasma Membranes ◽  
Acyl Chain ◽  
Md Simulations ◽  
Receptor Activation ◽  
Transmembrane Domains ◽  
Coarse Grained ◽  
Self Association ◽  
Lipid Protein Interactions

Clustering of transmembrane proteins underlies a multitude of fundamental biological processes at the plasma membrane such as receptor activation, lateral domain formation and mechanotransduction. The self-association of the respective transmembrane domains (TMD) has also been suggested to be responsible for the micron-scaled patterns seen for integral membrane proteins in the budding yeast plasma membrane (PM). However, the underlying interplay between local lipid composition and TMD identity is still not mechanistically understood. In this work we have used coarse-grained molecular dynamics (MD) simulations as well as microscopy experiments (TIRFM) to analyze the behavior of a representative helical yeast TMD (Slg1) within different lipid environments. Via the simulations we evaluated the effect of acyl chain saturation and the presence of anionic lipids head groups on the association of TMDs via simulations. Our simulations revealed that weak lipid-protein interactions significantly affect the configuration of TMD dimers and the free energy of association. Increased amounts of unsaturated phospholipids strongly reduced helix-helix interaction and the presence of phosphatidylserine (PS) lipids only slightly affected the dimer. Experimentally, the network factor, characterizing the association strength on a mesoscopic level, was measured in the presence and absence of PS lipids. Consistently with the simulations, no significant effect was observed. We also found that formation of TMD dimers in turn increased the order parameter of the surrounding lipids and induced long-range perturbations in lipid organization, shedding new light on the lipid-mediated dimerization of TMDs in complex lipid mixtures.

scholarly journals Transcriptome-wide Cas13 guide RNA design for model organisms and viral RNA pathogens

2020 ◽  
Author(s):  
Xinyi Guo ◽  
Hans-Hermann Wessels ◽  
Alejandro Méndez-Mancilla ◽  
Daniel Haro ◽  
Neville E. Sanjana
Keyword(s):  
Rna Virus ◽  
H1n1 Influenza ◽  
Model Organisms ◽  
Messenger Rnas ◽  
Protein Coding ◽  
Guide Rna ◽  
Knock Down ◽  
Guide Rnas ◽  
Rna Targeting ◽  
Rna Design

AbstractCRISPR-Cas13 mediates robust transcript knockdown in human cells through direct RNA targeting. Compared to DNA-targeting CRISPR enzymes like Cas9, RNA targeting by Cas13 is transcript- and strand-specific: It can distinguish and specifically knock-down processed transcripts, alternatively spliced isoforms and overlapping genes, all of which frequently serve different functions. Previously, we identified optimal design rules for RfxCas13d guide RNAs (gRNAs), and developed a computational model to predict gRNA efficacy for all human protein-coding genes. However, there is a growing interest to target other types of transcripts, such as noncoding RNAs (ncRNAs) or viral RNAs, and to target transcripts in other commonly-used organisms. Here, we predicted relative Cas13-driven knock-down for gRNAs targeting messenger RNAs and ncRNAs in six model organisms (human, mouse, zebrafish, fly, nematode and flowering plants) and four abundant RNA virus families (SARS-CoV-2, HIV-1, H1N1 influenza and MERS). To allow for more flexible gRNA efficacy prediction, we also developed a web-based application to predict optimal gRNAs for any RNA target entered by the user. Given the lack of Cas13 guide design tools, we anticipate this resource will facilitate CRISPR-Cas13 RNA targeting in common model organisms, emerging viral threats to human health, and novel RNA targets.

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