scholarly journals Mechanical Flexibility of DNA: A Quintessential Tool for DNA Nanotechnology

Sensors ◽  
2020 ◽  
Vol 20 (24) ◽  
pp. 7019
Author(s):  
Runjhun Saran ◽  
Yong Wang ◽  
Isaac T. S. Li
Keyword(s):  
Small Molecules ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Dna Nanotechnology ◽  
Bending Rigidity ◽  
Intrinsic Factors ◽  
Cellular Processes ◽  
Molecular Force ◽  
Sensory Element ◽  
Molecular Springs

The mechanical properties of DNA have enabled it to be a structural and sensory element in many nanotechnology applications. While specific base-pairing interactions and secondary structure formation have been the most widely utilized mechanism in designing DNA nanodevices and biosensors, the intrinsic mechanical rigidity and flexibility are often overlooked. In this article, we will discuss the biochemical and biophysical origin of double-stranded DNA rigidity and how environmental and intrinsic factors such as salt, temperature, sequence, and small molecules influence it. We will then take a critical look at three areas of applications of DNA bending rigidity. First, we will discuss how DNA’s bending rigidity has been utilized to create molecular springs that regulate the activities of biomolecules and cellular processes. Second, we will discuss how the nanomechanical response induced by DNA rigidity has been used to create conformational changes as sensors for molecular force, pH, metal ions, small molecules, and protein interactions. Lastly, we will discuss how DNA’s rigidity enabled its application in creating DNA-based nanostructures from DNA origami to nanomachines.

scholarly journals Peptide Targeting of PDZ-Dependent Interactions as Pharmacological Intervention in Immune-Related Diseases

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6367
Author(s):  
Luis H. Gutiérrez-González ◽  
Selma Rivas-Fuentes ◽  
Silvia Guzmán-Beltrán ◽  
Angélica Flores-Flores ◽  
Jorge Rosas-García ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Protein Protein Interactions ◽  
Pdz Proteins ◽  
Immune Evasion Mechanism ◽  
Cellular Processes ◽  
Clinical Conditions ◽  
Peptide Targeting

PDZ (postsynaptic density (PSD95), discs large (Dlg), and zonula occludens (ZO-1)-dependent interactions are widely distributed within different cell types and regulate a variety of cellular processes. To date, some of these interactions have been identified as targets of small molecules or peptides, mainly related to central nervous system disorders and cancer. Recently, the knowledge of PDZ proteins and their interactions has been extended to various cell types of the immune system, suggesting that their targeting by viral pathogens may constitute an immune evasion mechanism that favors viral replication and dissemination. Thus, the pharmacological modulation of these interactions, either with small molecules or peptides, could help in the control of some immune-related diseases. Deeper structural and functional knowledge of this kind of protein–protein interactions, especially in immune cells, will uncover novel pharmacological targets for a diversity of clinical conditions.

scholarly journals Obtaining Precise Molecular Information via DNA Nanotechnology

Membranes ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 683
Author(s):  
Qian Tang ◽  
Da Han
Keyword(s):  
Protein Interactions ◽  
Measurement Techniques ◽  
Protein Structures ◽  
Dna Nanotechnology ◽  
Molecular Structures ◽  
Protein Protein Interactions ◽  
Biochemical Processes ◽  
Molecular Force ◽  
Molecular Information ◽  
Resolution Of Imaging

Precise characterization of biomolecular information such as molecular structures or intermolecular interactions provides essential mechanistic insights into the understanding of biochemical processes. As the resolution of imaging-based measurement techniques improves, so does the quantity of molecular information obtained using these methodologies. DNA (deoxyribonucleic acid) molecule have been used to build a variety of structures and dynamic devices on the nanoscale over the past 20 years, which has provided an accessible platform to manipulate molecules and resolve molecular information with unprecedented precision. In this review, we summarize recent progress related to obtaining precise molecular information using DNA nanotechnology. After a brief introduction to the development and features of structural and dynamic DNA nanotechnology, we outline some of the promising applications of DNA nanotechnology in structural biochemistry and in molecular biophysics. In particular, we highlight the use of DNA nanotechnology in determination of protein structures, protein–protein interactions, and molecular force.

A Structural Perspective on the Modulation of Protein-Protein Interactions with Small Molecules

2018 ◽  
Vol 18 (8) ◽  
pp. 700-713 ◽  
Author(s):  
Habibe Cansu Demirel ◽  
Tunca Dogan ◽  
Nurcan Tuncbag
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Hot Spots ◽  
Rational Design ◽  
Structural Information ◽  
Enzymatic Reactions ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Structural Methods

Protein-Protein Interactions (PPIs) are the key components in many cellular processes including signaling pathways, enzymatic reactions and epigenetic regulation. Abnormal interactions of some proteins may be pathogenic and cause various disorders including cancer and neurodegenerative diseases. Although inhibiting PPIs with small molecules is a challenging task, it gained an increasing interest because of its strong potential for drug discovery and design. The knowledge of the interface as well as the structural and chemical characteristics of the PPIs and their roles in the cellular pathways is necessary for a rational design of small molecules to modulate PPIs. In this study, we review the recent progress in the field and detail the physicochemical properties of PPIs including binding hot spots with a focus on structural methods. Then, we review recent approaches for structural prediction of PPIs. Finally, we revisit the concept of targeting PPIs from a systems biology perspective and we refer to approaches that are usually employed when the structural information is not present.

scholarly journals E3 Ubiquitin Ligase SPL2 Is a Lanthanide-Binding Protein

2021 ◽  
Vol 22 (11) ◽  
pp. 5712
Author(s):  
Michał Tracz ◽  
Ireneusz Górniak ◽  
Andrzej Szczepaniak ◽  
Wojciech Białek
Keyword(s):  
Ubiquitin Ligase ◽  
Conformational Changes ◽  
Protein Interactions ◽  
E3 Ubiquitin Ligase ◽  
Lanthanide Ions ◽  
E3 Ligases ◽  
Fluorescence Measurements ◽  
Partial Unfolding

The SPL2 protein is an E3 ubiquitin ligase of unknown function. It is one of only three types of E3 ligases found in the outer membrane of plant chloroplasts. In this study, we show that the cytosolic fragment of SPL2 binds lanthanide ions, as evidenced by fluorescence measurements and circular dichroism spectroscopy. We also report that SPL2 undergoes conformational changes upon binding of both Ca2+ and La3+, as evidenced by its partial unfolding. However, these structural rearrangements do not interfere with SPL2 enzymatic activity, as the protein retains its ability to auto-ubiquitinate in vitro. The possible applications of lanthanide-based probes to identify protein interactions in vivo are also discussed. Taken together, the results of this study reveal that the SPL2 protein contains a lanthanide-binding site, showing for the first time that at least some E3 ubiquitin ligases are also capable of binding lanthanide ions.

scholarly journals Global mapping of protein–metabolite interactions in Saccharomyces cerevisiae reveals that Ser-Leu dipeptide regulates phosphoglycerate kinase activity

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Marcin Luzarowski ◽  
Rubén Vicente ◽  
Andrei Kiselev ◽  
Mateusz Wagner ◽  
Dennis Schlossarek ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Small Molecules ◽  
Phosphoglycerate Kinase ◽  
Glycolytic Enzyme ◽  
Diauxic Shift ◽  
Cellular Processes ◽  
Targeted Analysis ◽  
Global Mapping ◽  
Biochemical Approach ◽  
User Friendly

AbstractProtein–metabolite interactions are of crucial importance for all cellular processes but remain understudied. Here, we applied a biochemical approach named PROMIS, to address the complexity of the protein–small molecule interactome in the model yeast Saccharomyces cerevisiae. By doing so, we provide a unique dataset, which can be queried for interactions between 74 small molecules and 3982 proteins using a user-friendly interface available at https://promis.mpimp-golm.mpg.de/yeastpmi/. By interpolating PROMIS with the list of predicted protein–metabolite interactions, we provided experimental validation for 225 binding events. Remarkably, of the 74 small molecules co-eluting with proteins, 36 were proteogenic dipeptides. Targeted analysis of a representative dipeptide, Ser-Leu, revealed numerous protein interactors comprising chaperones, proteasomal subunits, and metabolic enzymes. We could further demonstrate that Ser-Leu binding increases activity of a glycolytic enzyme phosphoglycerate kinase (Pgk1). Consistent with the binding analysis, Ser-Leu supplementation leads to the acute metabolic changes and delays timing of a diauxic shift. Supported by the dipeptide accumulation analysis our work attests to the role of Ser-Leu as a metabolic regulator at the interface of protein degradation and central metabolism.

scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Marie Adams ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Methylation Array ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

AbstractBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

scholarly journals Purification, crystallization and preliminary X-ray crystallographic studies of FMN-bound and FMN-free forms of aromatic acid decarboxylase (CpsUbiX) from the psychrophilic bacteriumColwellia psychrerythraea34H

2014 ◽  
Vol 70 (2) ◽  
pp. 215-220 ◽  
Author(s):  
Hackwon Do ◽  
Chang Woo Lee ◽  
Se Jong Han ◽  
Sung Gu Lee ◽  
Hak Jun Kim ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Aromatic Acid ◽  
Diffusion Method ◽  
Flavin Mononucleotide ◽  
Acid Decarboxylase ◽  
Data Sets ◽  
Single Mutation ◽  
Homologous Proteins ◽  
Space Group

TheubiXgene (UniProtKB code Q489U8) ofColwellia psychrerythraeastrain 34H has been annotated as a putative flavin mononucleotide (FMN)-dependent aromatic acid decarboxylase. Based on previous studies of homologous proteins, CpsUbiX is thought to catalyze the decarboxylation of 3-octaprenyl-4-hydroxybenzoate to produce 2-polyprenylphenol in the ubiquinone-biosynthesis pathway using a noncovalently bound FMN molecule as a cofactor. However, the detailed mechanisms of this important enzyme are not yet clear and need to be further elucidated. In this study, it was found that the V47S single mutation resulted in a loss of FMN binding, resulting in the production of FMN-free CpsUbiX protein. This mutation is likely to destabilize FMN–protein interactions without affecting the overall structural folding. To fully characterize the conformational changes upon FMN binding and the enzymatic mechanism at the molecular level, the wild-type (FMN-bound) and V47S mutant (FMN-free) CpsUbiX proteins were purified and crystallized using the sitting-drop vapour-diffusion method. Furthermore, complete diffraction data sets for FMN-bound (space groupC2221) and FMN-free (space groupP23) forms were obtained to 2.0 and 1.76 Å resolution, respectively.

Visual detection of binary, ternary, and quaternary protein interactions in fission yeast by Pil1 co-tethering assay

2021 ◽  
Author(s):  
Zhong-Qiu Yu ◽  
Xiao-Man Liu ◽  
Dan Zhao ◽  
Dan-Dan Xu ◽  
Li-Lin Du
Keyword(s):  
Fission Yeast ◽  
Protein Interactions ◽  
Visual Detection ◽  
Protein Protein Interactions ◽  
Phosphatidylinositol 3 Kinase ◽  
Basic Form ◽  
Bait Protein ◽  
Cellular Processes ◽  
Prey Protein ◽  
Versatile Tool

Protein-protein interactions are vital for executing nearly all cellular processes. To facilitate the detection of protein-protein interactions in living cells of the fission yeast Schizosaccharomyces pombe, here we present an efficient and convenient method termed the Pil1 co-tethering assay. In its basic form, we tether a bait protein to mCherry-tagged Pil1, which forms cortical filamentary structures, and examine whether a GFP-tagged prey protein colocalizes with the bait. We demonstrate that this assay is capable of detecting pairwise protein-protein interactions of cytosolic proteins and nuclear proteins. Furthermore, we show that this assay can be used for detecting not only binary protein-protein interactions, but also ternary and quaternary protein-protein interactions. Using this assay, we systematically characterized the protein-protein interactions in the Atg1 complex and in the phosphatidylinositol 3-kinase (PtdIns3K) complexes and found that Atg38 is incorporated into the PtdIns3K complex I via an Atg38-Vps34 interaction. Our data show that this assay is a useful and versatile tool and should be added to the routine toolbox of fission yeast researchers.

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