Category Archives: Israel Journal of Chemistry

Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

Posted on 19 January 2024 by nRyan R. Cupo, nJames Shortern

Abstract

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.

Tuning the Sign and Magnitude of Complexation‐Induced pKa Shifts in Cucurbit[7]uril Host‐Guest Complexes by Molecular Engineering

Posted on 9 January 2024 by

Abstract

Cucurbiturils are popular macrocyclic receptors that bind complementary guest molecules with high affinity in aqueous environments. They are recognized for their ability to selectively bind positively charged guest molecules, including ionizable ammonium cations which frequently display much higher affinity than their neutral counterparts. This selectivity for the protonated species is translated into an increase in the basicity of encapsulated guests (i. e. into complexation-induced positive pK _a shifts). However, despite being very rare, negative pK _a shifts can be observed for specific guests. Following a previous work from our group reporting slightly negative pK _a shifts for flavylium and chalcone dyes featuring N-diethylamino substituents (ΔpK _a=− 0.2), herein we report a systematic study on the complexation of N-dialkylaminochalcones with CB7. The results show that the pK _a shifts of these host-guest complexes can be rationally tuned by the nature of the N-dialkylamino groups and as well by target substitutions on the skeleton of the dye, allowing the design of a CB7 1 : 1 host-guest complex with a ΔpK _a=− 0.6.

Superconducting Quasicrystals

Posted on 3 January 2024 by nNayuta Takemorin

Abstract

Dan Shechtman's discovery of quasicrystals in 1982 introduced the scientific world to aperiodic crystals with unique rotational symmetries, redefining traditional crystallography. Although superconductivity in related periodic approximants has since been observed, true bulk superconductivity in quasicrystals was confirmed only in 2018. This recent discovery opens a new horizon not only for the study of correlated quasicrystals but more generally for the study of superconductivity with nontrivial spatial order. The theoretical understanding of superconducting quasicrystals poses challenges due to their lack of periodicity. Notably, they exhibit non-BCS type superconductivity and distinct electromagnetic responses, reminiscent of the so-called FFLO state. In this review, we provide an overview of superconducting quasicrystals, along with some “behind-the-scenes” information.

Fabricating Quasiperiodic Tilings with Thermal‐Scanning Probe Lithography

Posted on 11 December 2023 by

Abstract

We outline an approach to fabricate nanoscale artificial quasiperiodic tilings with thermal-scanning probe lithography. Quasiperiodic tilings such as the Ammann-Beenker, Square Fibonacci tiling, and Penrose are fabricated and imaged with thermal-conductance feedback microscopy, followed by electron microscopy. The design implementation, chemical, and physical challenges involved in fabricating such artificial systems using nanolithography are discussed. Additionally, the potential applications of fabricated quasiperiodic tilings are explored.

Quasicrystalline Antimony Thin Films

Posted on 30 November 2023 by nHem Raj Sharma, nPeter John Nugent, nSam Coates, nRonan McGrathn

Abstract

The growth of antimony (Sb) thin films on the fivefold surface of icosahedral Ag−In−Yb quasicrystal has been studied by scanning tunneling microscopy (STM) and x-ray photoelectron spectroscopy (XPS). At low coverage, the deposited Sb yields a network of pentagons of different sizes and heights. These Sb pentagons can be mapped by a pentagonal tiling of the substrate and thus exhibit quasicrystalline long-range order. Subsequent deposition of Sb yields a disordered film. XPS observations of the growth mode are consistent with the STM results.

STEM Structural Investigation of RE‐Au‐Si 1/1 Approximants

Posted on 14 November 2023 by

Abstract

RE-Au-Si (RE=Ho, Tb) systems are 1/1 Tsai-type quasicrystalline approximants with a cluster center decoration that can vary from a disordered tetrahedron to a rare-earth atom. The local atomic structure of three different samples was observed by scanning transmission electron microscopy and interpreted in the light of high-angle annular dark field simulated scanning transmission electron microscopy images. It is found that the combination of these two methods allows to identify differences in the chemical decoration of the cluster centers through quantitative analysis of line profiles.

Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation

Posted on 8 November 2023 by

Abstract

The NLRP3 inflammasome is a cytosolic protein complex that regulates innate immune signaling in response to diverse pathogenic insults through the proteolytic processing and secretion of pro-inflammatory cytokines such as IL-1β. Hyperactivation of NLRP3 inflammasome signaling is implicated in the onset and pathogenesis of numerous diseases, motivating the discovery of new strategies to suppress NLRP3 inflammasome activity. We sought to define the potential for the proteostasis regulator AA147 to inhibit the assembly and activation of the NLRP3 inflammasome. AA147 is a pro-drug that is metabolically converted to a reactive metabolite at the endoplasmic reticulum (ER) membrane to covalently modify ER-localized proteins such as protein disulfide isomerases (PDIs). We show that AA147 inhibits NLRP3 inflammasome activity in monocytes and monocyte-derived macrophages through a mechanism involving impaired assembly of the active inflammasome complex. This inhibition is mediated through AA147-dependent covalent modification of PDIA1. Genetic depletion or treatment with other highly selective PDIA1 inhibitors similarly blocks NLRP3 inflammasome assembly and activation. Our results identify PDIA1 as a potential therapeutic target to mitigate NLRP3 inflammasome-mediated pro-inflammatory signaling implicated in etiologically diverse diseases.

The Role of the Proteasome in Limiting Cellular Stress Associated with Protein Accumulation

Posted on 7 November 2023 by nKate A. Kragness, nDarci J. Tradern

Abstract

The proteasome is comprised of multiple subunits that catalyze the degradation of proteins to maintain cellular homeostasis. The proteasome targets protein substrates by two different pathways. The ubiquitin-dependent pathway requires proteins to be labeled with a ubiquitin tag to signal for degradation by the 26S isoform of the proteasome. Protein degradation through this pathway declines during age progression. The ubiquitin-independent pathway utilizes the 20S proteasome isoform. It can degrade misfolded and intrinsically disordered proteins to decrease cellular stress. Age-related protein accumulation and aggregation can occur due to the decreased activity and expression of the proteasome. Protein accumulation causes increased cellular stress which can contribute to disease progression. Increasing proteasome activity could serve as a solution to eliminating and preventing protein accumulation. Studies have shown the value of the proteasome as a therapeutic entity to mitigate cellular stress. This perspective explores the link between proteasome activity and cellular stress caused by age-related misfolded protein accumulation.

Understanding and Overcoming Biochemical Diversity in AL Amyloidosis

Posted on 6 November 2023 by nGareth J. Morgann

Abstract

Amyloid fibril deposition causes progressive tissue damage and organ failure in the systemic amyloid diseases, and therapies that suppress aggregation lead to clinical benefit. Small molecules that prevent aggregation by binding to precursor proteins are effective for amyloid transthyretin (ATTR) amyloidosis. However, in amyloid light chain (AL) amyloidosis, fibrils are formed by antibody light chains and every patient has a unique protein sequence that aggregates. The highly diverse sequences of these light chains appear to determine whether an individual is at risk of amyloidosis, the distribution of amyloid deposits and the progression of disease. Light chains are therefore challenging drug targets. This review explores the parallels between AL amyloidosis and ATTR amyloidosis to describe the discovery of small molecules that can stabilize light chains. These molecules have potential as therapies for AL amyloidosis, highlighting potential opportunities for drug discovery in other diseases of protein misfolding.

Scanning Tunnelling Microscopy Studies of Tsai‐Type Quasicrystal Approximants

Posted on 2 November 2023 by nSam Coates, nDominic Burnie, nHem Raj Sharma, nRonan McGrathn

Abstract

We review scanning tunnelling microscopy (STM) studies of the surfaces of periodic Tsai-type approximants. Although they are useful analogues to the Tsai-type quasicrystals, the surfaces of these periodic approximants behave in subtly different and often more complex ways when compared to their quasiperiodic cousins. We present a summary of STM studies conducted upon Tsai-type approximants; we discuss the various differences and similarities between phases and surface directions, and compare these to the surfaces of the related quasicrystalline phases. We also present open questions which have been raised by these studies, and offer potential routes to answer them.