Is allostery a fuzzy concept?

Allostery is an important property of biological macromolecules which regulates diverse biological functions such as catalysis, signal transduction, transport, and molecular recognition. However, the concept was expressed using two different definitions by J. Monod and, over time, more have been added by different authors, making it fuzzy.

Investigation of the Entry Pathway and Molecular Nature of σ1 Receptor Ligands.

The σ1 receptor (σ1-R) is an enigmatic endoplasmic reticulum resident transmembrane protein implicated in a variety of central nervous system disorders and whose agonists have neuroprotective activity. In spite of σ1-R's physio-pathological and pharmacological importance, two of the most important features required to fully understand σ1-R function, namely the receptor endogenous ligand(s) and the molecular mechanism of ligand access to the binding site, have not yet been unequivocally determined. In this work, we performed molecular dynamics (MD) simulations to help clarify the potential route of access of ligand(s) to the σ1-R binding site, on which discordant results had been reported in the literature.

Arabidopsis thaliana sirtuins control proliferation and glutamate dehydrogenase activity.

Sirtuins are part of a gene family of NAD-dependent deacylases that act on histone and non-histone proteins and control a variety of activities in all living organisms. Their roles are mainly related to energy metabolism and include lifetime regulation, DNA repair, stress resistance, and proliferation. A large amount of knowledge concerning animal sirtuins is available, but data about their plant counterparts are scarce.

Structural Basis of Sequential and Concerted Cooperativity.

Allostery is a property of biological macromolecules featuring cooperative ligand binding and regulation of ligand affinity by effectors. The definition was introduced by Monod and Jacob in 1963, and formally developed as the "concerted model" by Monod, Wyman, and Changeux in 1965. Since its inception, this model of cooperativity was seen as distinct from and not reducible to the "sequential model" originally formulated by Pauling in 1935, which was developed further by Koshland, Nemethy, and Filmer in 1966.

Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin.

Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (>35 copies) of a CAG triplet located in exon 1 of the gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that in turn leads to neuronal injury and apoptosis. Therefore, both the inhibition of mHtt aggregate formation and the acceleration of mHtt degradation represent attractive strategies to delay HD progression, and even for HD treatment.

Arabidopsis N-acetyltransferase activity 2 preferentially acetylates 1,3-diaminopropane and thialysine.

Polyamine acetylation has an important regulatory role in polyamine metabolism. It is catalysed by GCN5-related N-acetyltransferases, which transfer acetyl groups from acetyl-coenzyme A to the primary amino groups of spermidine, spermine (Spm), or other polyamines and diamines, as was shown for the human Spermidine/Spermine N-acetyltransferase 1 (HsSSAT1). SSAT homologues specific for thialysine, a cysteine-derived lysine analogue, were also identified (e.

AI applications in functional genomics.

We review the current applications of artificial intelligence (AI) in functional genomics. The recent explosion of AI follows the remarkable achievements made possible by "deep learning", along with a burst of "big data" that can meet its hunger. Biology is about to overthrow astronomy as the paradigmatic representative of big data producer.

Exploring the Ability of LARS2 Carboxy-Terminal Domain in Rescuing the MELAS Phenotype.

The m.3243A>G mutation within the mitochondrial mt-tRNALeu gene is the most prevalent variant linked to mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome. This pathogenic mutation causes severe impairment of mitochondrial protein synthesis due to alterations of the mutated tRNA, such as reduced aminoacylation and a lack of post-transcriptional modification.

Neuropilin-1 is required for endothelial cell adhesion to soluble vascular endothelial growth factor receptor 1.

Neuropilin-1 (NRP-1) is a semaphorin receptor involved in neuron guidance, and a co-receptor for selected isoforms of the vascular endothelial growth factor (VEGF) family. NRP-1 binding to several VEGF-A isoforms promotes growth factor interaction with VEGF receptor (VEGFR)-2, increasing receptor phosphorylation. Additionally, NRP-1 directly interacts with VEGFR-1, but this interaction competes with NRP-1 binding to VEGF-A165 and does not enhance VEGFR-1 activation.

High activity and low toxicity of a novel CD71-targeting nanotherapeutic named The-0504 on preclinical models of several human aggressive tumors.

Background: Ferritin receptor (CD71) is an example of a very attractive cancer target, since it is highly expressed in virtually all tumor types, including metastatic loci. However, this target can be considered to be inaccessible to conventional target therapies, due to its presence in many healthy tissues. Here, we describe the preclinical evaluation of a tumor proteases-activatable human ferritin (HFt)-based drug carrier (The-0504) that is able to selectively deliver the wide-spectrum topoisomerase I inhibitor Genz-644282 to CD71-expressing tumors, preventing the limiting toxic effects associated with CD71-targeting therapies.

Known Drugs Identified by Structure-Based Virtual Screening Are Able to Bind Sigma-1 Receptor and Increase Growth of Huntington Disease Patient-Derived Cells.

Huntington disease (HD) is a devastating and presently untreatable neurodegenerative disease characterized by progressively disabling motor and mental manifestations. The sigma-1 receptor (σ1R) is a protein expressed in the central nervous system, whose 3D structure has been recently determined by X-ray crystallography and whose agonists have been shown to have neuroprotective activity in neurodegenerative diseases. To identify therapeutic agents against HD, we have implemented a drug repositioning strategy consisting of: (i) Prediction of the ability of the FDA-approved drugs publicly available through the ZINC database to interact with σ1R by virtual screening, followed by computational docking and visual examination of the 20 highest scoring drugs; and (ii) Assessment of the ability of the six drugs selected by computational analyses to directly bind purified σ1R in vitro by Surface Plasmon Resonance and improve the growth of fibroblasts obtained from HD patients, which is significantly impaired with respect to control cells.

Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy.

Gastrointestinal tumors, including pancreatic and colorectal cancers, represent one of the greatest public health issues worldwide, leading to a million global deaths. Recent research demonstrated that the human heavy chain ferritin (HFt) can encapsulate different types of drugs in its cavity and can bind to its receptor, CD71, in several solid and hematological tumors, thus highlighting the potential use of ferritin for tumor-targeting therapies. Here, we describe the development and characterization of a novel nanomedicine based on the HFt that is named The-0504.

Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects.

Mutations in mitochondrial transfer RNA (mt-tRNA) genes are responsible for a wide range of syndromes, for which no effective treatment is available. We previously reported that transfection of the nucleotide sequence encoding for the 16-residue β32_33 peptide from mitochondrial leucyl-tRNA synthetase ameliorates the cell phenotype caused by the mitochondrial tRNA mutations. In this work, we demonstrated that both the β32_33 peptide linked with the known (L)-Phe-(D)-Arg-(L)-Phe-(L)-Lys (FrFK) mitochondrial penetrating sequence and, strikingly, the β32_33 peptide per se, are able to penetrate both the plasma and mitochondrial membranes and exert the rescuing activity when exogenously administered to cells bearing the mutations m.

Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington's disease therapy.

Huntington's disease (HD) is a lethal neurodegenerative disorder for which no cure is available yet. It is caused by abnormal expansion of a CAG triplet in the gene encoding the huntingtin protein (Htt), with consequent expansion of a polyglutamine repeat in mutated Htt (mHtt). This makes mHtt highly unstable and aggregation prone.

Protein Engineering of Multi-Modular Transcription Factor Alcohol Dehydrogenase Repressor 1 (Adr1p), a Tool for Dissecting In Vitro Transcription Activation.

Studying transcription machinery assembly is challenging because of long intrinsically disordered regions present within the multi-modular transcription factors. One example is alcohol dehydrogenase repressor 1 (Adr1p) from fermenting yeast, responsible for the metabolic switch from glucose to ethanol. The role of each individual transcription activation domain (TAD) has been previously studied, but their interplay and their roles in enhancing the stability of the protein is not known.

A novel resveratrol derivative induces mitotic arrest, centrosome fragmentation and cancer cell death by inhibiting γ-tubulin.

Background: Resveratrol and its natural stilbene-containing derivatives have been extensively investigated as potential chemotherapeutic agents. The synthetic manipulation of the stilbene scaffold has led to the generation of new analogues with improved anticancer activity and better bioavailability. In the present study we investigated the anticancer activity of a novel trimethoxystilbene derivative (3,4,4'-trimethoxylstilbene), where two methoxyl groups are adjacent on the benzene ring (ortho configuration), and compared its activity to 3,5,4'-trimethoxylstilbene, whose methoxyl groups are in meta configuration.

Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement.

Primary mitochondrial dysfunction is an under-appreciated cause of cardiomyopathy, especially when cardiac symptoms are the unique or prevalent manifestation of disease. Here, we report an unusual presentation of mitochondrial cardiomyopathy, with dilated phenotype and pathologic evidence of biventricular fibro-adipose replacement, in a 33-year old woman who underwent cardiac transplant. Whole exome sequencing revealed two novel compound heterozygous variants in the TSFM gene, coding for the mitochondrial translation elongation factor EF-Ts.

Positive and Negative Regulation of Angiogenesis by Soluble Vascular Endothelial Growth Factor Receptor-1.

Vascular endothelial growth factor receptor (VEGFR)-1 exists in different forms, derived from alternative splicing of the same gene. In addition to the transmembrane form, endothelial cells produce a soluble VEGFR-1 (sVEGFR-1) isoform, whereas non-endothelial cells produce both sVEGFR-1 and a different soluble molecule, known as soluble fms-like tyrosine kinase (sFlt)1-14. By binding members of the vascular endothelial growth factor (VEGF) family, the soluble forms reduce the amounts of VEGFs available for the interaction with their transmembrane receptors, thereby negatively regulating VEGFR-mediated signaling.

Glucose transportation in the brain and its impairment in Huntington disease: one more shade of the energetic metabolism failure?

Huntington's disease (HD) or Huntington's chorea is the most common inherited, dominantly transmitted, neurodegenerative disorder. It is caused by increased CAG repeats number in the gene coding for huntingtin (Htt) and characterized by motor, behaviour and psychiatric symptoms, ultimately leading to death. HD patients also exhibit alterations in glucose and energetic metabolism, which result in pronounced weight loss despite sustained calorie intake.

Proteomic and functional analyses reveal pleiotropic action of the anti-tumoral compound NBDHEX in Giardia duodenalis.

Giardiasis, a parasitic diarrheal disease caused by Giardia duodenalis, affects one billion people worldwide. Treatment relies only on a restricted armamentarium of drugs. The disease burden and the increase in treatment failure highlight the need for novel, safe and well characterized drug options.

Drosophila CG3303 is an essential endoribonuclease linked to TDP-43-mediated neurodegeneration.

Endoribonucleases participate in almost every step of eukaryotic RNA metabolism, acting either as degradative or biosynthetic enzymes. We previously identified the founding member of the Eukaryotic EndoU ribonuclease family, whose components display unique biochemical features and are flexibly involved in important biological processes, such as ribosome biogenesis, tumorigenesis and viral replication. Here we report the discovery of the CG3303 gene product, which we named DendoU, as a novel family member in Drosophila.

Antitumor activity of a novel anti-vascular endothelial growth factor receptor-1 monoclonal antibody that does not interfere with ligand binding.

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase transmembrane receptor that has also a soluble isoform containing most of the extracellular ligand binding domain (sVEGFR-1). VEGF-A binds to both VEGFR-2 and VEGFR-1, whereas placenta growth factor (PlGF) interacts exclusively with VEGFR-1. In this study we generated an anti-VEGFR-1 mAb (D16F7) by immunizing BALB/C mice with a peptide that we had previously reported to inhibit angiogenesis and endothelial cell migration induced by PlGF.

Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness.

Human ferritin heavy chain (HFt) has been demonstrated to possess considerable potential for targeted delivery of drugs and diagnostic agents to cancer cells. Here, we report the development of a novel HFt-based genetic construct (HFt-MP-PAS) containing a short peptide linker (MP) between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). The peptide linker contains a matrix-metalloproteinases (MMPs) cleavage site that permits the protective PAS shield to be removed by tumor-driven proteolytic cleavage within the tumor microenvironment.

Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations.

Mutations in mitochondrial (mt) genes coding for mt-tRNAs are responsible for a range of syndromes, for which no effective treatment is available. We recently showed that the carboxy-terminal domain (Cterm) of human mt-leucyl tRNA synthetase rescues the pathologic phenotype associated either with the m.3243A>G mutation in mt-tRNA(Leu(UUR)) or with mutations in the mt-tRNA(Ile), both of which are aminoacylated by Class I mt-aminoacyl-tRNA synthetases (mt-aaRSs).