Israel Journal of Chemistry最新文献

The unfolded protein response (UPR) is a sensing and signaling pathway that surveys the endoplasmic reticulum (ER) for protein folding challenges and responds whenever issues are detected. UPR activation leads to upregulation of secretory pathway chaperones and quality control factors, as well as reduces the nascent protein load on the ER, thereby restoring and maintaining proteostasis. This paradigm-defining view of the role of the UPR is accurate, but it elides additional key functions of the UPR in cell biology. In particular, recent work has revealed that the UPR can shape the structure and function of N- and O-glycans installed on ER client proteins. This crosstalk between the UPR's reaction to protein misfolding and the regulation of glycosylation remains insufficiently understood. Still, emerging evidence makes it clear that the UPR, and particularly the IRE1-XBP1s arm of the UPR, may be a central regulator of protein glycosylation, with important biological consequences. In this review, we discuss the crosstalk between proteostasis, the UPR, and glycosylation, present progress towards understanding biological functions of this crosstalk, and examine potential roles in diseases such as cancer.

We investigate the Ising model on the Bronze-mean hexagonal quasicrystal (BMH QC), an aperiodic tiling with geometric frustration. Our extensive Monte Carlo simulations explore the model's rich phase diagram, revealing six distinct phases with diverse magnetic properties and degrees of frustration. We uncover exotic spin glass phases, signaled by the replica symmetry breaking and slow relaxation dynamics. We shed light on the intriguing magnetic properties of frustrated quasicrystals and open new avenues for studying exotic phases in condensed matter physics.

Sequencing for RNA modifications with the nanopore direct RNA sequencing platform provides ionic current levels, helicase dwell times, and base call data that differentiate the modifications from the canonical form. Herein, model RNAs were synthesized with site-specific uridine (U) base modifications that enable the study of increasing an alkyl group size, halogen identity, or a change in base acidity to impact the nanopore data. The analysis concluded that increases in alkyl size trend with greater current blockage but a similar change in base-call error was not found. The addition of a halogen series to C5 of U revealed that the current levels recorded a trend with the water-octanol partition coefficient of the base, as well as the base call error. Studies with U modifications that are deprotonated (i. e., anionic) under the sequencing conditions gave broad current levels that influenced the base call error. Some modifications led to helicase dwell time changes. These insights provide design parameters for modification-specific chemical reagents that can shift nanopore signatures to minimize false positive reads, a known issue with this sequencing approach.

Variants in the genes encoding gamma-aminobutyric acid type A (GABA_A) receptor subunits are associated with epilepsy. To date, over 1000 clinical variants have been identified in these genes. However, the majority of these variants lack functional studies and their clinical significance is uncertain although accumulating evidence indicates that proteostasis deficiency is the major disease-causing mechanism. Here, we apply two state-of-the-art modeling tools, namely AlphaMissense and Rhapsody to predict the pathogenicity of saturating missense variants in genes that encode the major subunits of GABA_A receptors in the central nervous system, including GABRA1, GABRB2, GABRB3, and GABRG2. We demonstrate that the predicted pathogenicity correlates well between AlphaMissense and Rhapsody. In addition, AlphaMissense pathogenicity score correlates modestly with plasma membrane expression, peak current amplitude, and GABA potency of the variants that have available experimental data. Furthermore, almost all annotated pathogenic variants in the ClinVar database are successfully identified from the prediction, whereas uncertain variants from ClinVar partially due to the lack of experimental data are differentiated into different pathogenicity groups. The pathogenicity prediction of GABA_A receptor missense variants provides a resource to the community as well as guidance for future experimental and clinical investigations.

Cystic Fibrosis (CF) is a genetic disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to a faulty CFTR protein. Dysfunctional CFTR causes chloride ion imbalance, resulting in dense mucus accumulation in various organs, particularly the lungs. CF treatments focus on symptom management and addressing CFTR′s functional defects. Notably, development of CFTR modulator therapies has significantly advanced CF treatment. These drugs target CFTR protein structural defects induced by mutations, restoring its function and improving CF symptoms. VX-770, a CFTR potentiator, and CFTR correctors like VX-809, VX-661, and VX-445, have gained FDA approval and widespread clinical use, greatly enhancing the health and survival of many CF patients. However, some CFTR mutations lack effective targeted therapies, leaving approximately 6 % of CF patients without suitable options. CFTR modulator therapies have proven essential for combating the underlying causes of protein misfolding diseases, serving as a blueprint for similar treatments in other membrane protein misfolding diseases. This review explores current and future CFTR modulator therapies, and applications of established paradigms to membrane protein misfolding diseases. Ongoing research and innovation hold the potential for further improvements in CF management and the treatment of protein misfolding diseases.

Genetically encoded peptide libraries are at the forefront of de novo drug discovery. The RaPID (Random Nonstandard Peptides Integrated Discovery) platform stands out due to the unique combination of flexible in vitro translation (FIT) and mRNA display. This enables the incorporation of non-canonical amino acids, improving chemical diversity and allowing macrocyclisation of the peptide library. The resulting constrained peptides are valued for their strong binding affinity and stability, especially in the context of protein-protein interactions. In response to SARS-CoV-2, the causative agent of the COVID-19 pandemic, the RaPID system proved valuable in identifying high-affinity ligands of viral proteins. Among many peptide ligands of SARS-CoV-2 spike and main protease (M^pro), several macrocycles stand out for their exceptional binding affinities. Structural data showcases distinct binding modes in complex with the receptor-binding domain (RBD) of the spike glycoprotein or the catalytic active site of M^pro. However, translating these in vitro findings into clinical applications remains challenging, especially due to insufficient cell permeability.

Protein folding is important for all life. Indeed, protein misfolding can result in catastrophic protein aggregation and toxicity. The pathways involved in reversing protein aggregation within human mitochondria had long been unknown. We recently discovered that Skd3 (human CLPB) is a potent mitochondrial protein disaggregase, which is regulated by the rhomboid protease PARL, and maintains the solubility of many important mitochondrial proteins. Skd3 variants underlie several debilitating human diseases, including 3-methylglutaconic aciduria, severe congenital neutropenia, and premature ovarian insufficiency. Here, we describe advances in understanding Skd3 function, mechanism, and structure and place these discoveries in the context of physiology and disease.

The cover picture shows a cartoon depicting an SHG setup in which an fs laser with a frequency of ω impinges onto the surface, leading to the nonlinear scattering of photons with double the frequency. This technique enables getting information from the metallic electrode surface while suppressing the data from the bulk due to symmetry considerations.

Surface characterization is essential for understanding chemical and electrochemical transformations occurring on surfaces or at interfaces. Battery electrode aging processes, biofilm growth, crystallization, and transport/signaling across cellular membranes are only a few examples of such phenomena. This special issue delves into applied electrochemistry and nonlinear optical techniques applicable to surface characterization.

Near-field techniques usually require specialized instrumentation. However, although much improvement has been made over recent years, many surface-characterization tools are still limited to samples in a vacuum; therefore, in-situ and in-operando experiments are impractical. On the other hand, optical techniques are more flexible and less demanding regarding sample handling. Still, they usually need more surface specificity and sensitivity, and in principle, they have a lower resolution compared to electron beam-based techniques.

On the other hand, optical techniques also offer different contrast modalities. For example, Second-harmonic generation (SHG) or surface-enhanced Raman spectroscopy (SERS) are versatile optical tools for probing surfaces. From symmetry considerations, SHG responses are forbidden from the bulk of metallic electrodes and observed only from the surface where the symmetry is broken. Thus, high sensitivity can be attained using SHG, and when both SHG and SERS are combined, selectivity and sensitivity can be achieved. In addition, nanofabrication of metallic surfaces can further improve the sensitivity of SHG and SERS by orders of magnitude due to local field enhancement.

In recent years, much improvement has been made in super-resolution microscopy and imaging, enabling fast yet high-resolution imaging over areas as large as half-by-half-millimeter squares. For the field of electrochemistry, such development is very important since it may open the door for real-time optical characterization of solid-liquid interfaces during charging/discharging cycles, which can potentially lead to significant improvements in the performance and durability of the electrode. These contributions not only expand the horizons of applied electrochemical science but also underline its influence on our daily lives and its pivotal role in addressing global challenges related to climate and energy.