The development of proteinase-activated receptor-2 modulators and the challenges involved.
Abstract Protease-activated receptor-2 (PAR2) has been extensively studied since its discovery in the mid-1990. Despite the advances in understanding PAR2 pharmacology, it has taken almost 25 years for the first inhibitor to reach clinical trials, and so far, no PAR2 antagonist has been approved for human use. Research has employed classical approaches to develop a wide array of PAR2 agonists and antagonists, consisting of peptides, peptoids and antibodies to name a few, with a surge in patent applications over this period. Recent breakthroughs in PAR2 structure determination has provided a unique insight into pro...
Source: Biochemical Society Transactions - November 26, 2020 Category: Biochemistry Authors: McIntosh KA, Cunningham MR, Bushell T, Plevin R Tags: Biochem Soc Trans Source Type: research

Solar-driven water-splitting provides a solution to the energy problem underpinning climate change.
Abstract The emergence of the oxygen-evolving photosystem two complex over 2.6 billion years ago represented the 'big bang of evolution' on planet Earth. It allowed phototrophic organisms to use sun light as an energy source to extract electrons and protons from water, and concomitantly release oxygen. Oxygenic photosynthesis not only created an aerobic atmosphere but also removed CO2 to produce the organic molecules that make up the current global biomass and fossil fuel. In addition, it paved the way for animal life. Today extensive burning of fossil fuels is reversing the results of photosynthesis through billi...
Source: Biochemical Society Transactions - November 26, 2020 Category: Biochemistry Authors: Barber J Tags: Biochem Soc Trans Source Type: research

Caveolin-1, tetraspanin CD81 and flotillins in lymphocyte cell membrane organization, signaling and immunopathology.
Abstract The adaptive immune system relies on B and T lymphocytes to ensure a specific and long-lasting protection of an individual from a wide range of potential pathogenic hits. Lymphocytes are highly potent and efficient in eliminating pathogens. However, lymphocyte activation must be tightly regulated to prevent incorrect activity that could result in immunopathologies, such as autoimmune disorders or cancers. Comprehensive insight into the molecular events underlying lymphocyte activation is of enormous importance to better understand the function of the immune system. It provides the basis to design therapeu...
Source: Biochemical Society Transactions - November 26, 2020 Category: Biochemistry Authors: Schaffer AM, Minguet S Tags: Biochem Soc Trans Source Type: research

KRASG12C inhibitor: combing for combination.
Abstract Oncogenic mutation in KRAS is one of the most common alterations in human cancer. After decades of extensive research and unsuccessful drug discovery programs, therapeutic targeting of KRAS mutant tumour is at an exciting juncture. The discovery of mutation-specific inhibitors of KRASG12C and early positive findings from clinical trials has raised the hope of finally having a drug to treat a significant segment of KRAS mutant cancer patients. Crucially, it has also re-energized the RAS field to look beyond G12C mutation and find new innovative targeting opportunities. However, the early clinical trial dat...
Source: Biochemical Society Transactions - November 26, 2020 Category: Biochemistry Authors: Chakraborty A Tags: Biochem Soc Trans Source Type: research

Engineering with NanoLuc: a playground for the development of bioluminescent protein switches and sensors.
Abstract The small engineered luciferase NanoLuc has rapidly become a powerful tool in the fields of biochemistry, chemical biology, and cell biology due to its exceptional brightness and stability. The continuously expanding NanoLuc toolbox has been employed in applications ranging from biosensors to molecular and cellular imaging, and currently includes split complementation variants, engineering techniques for spectral tuning, and bioluminescence resonance energy transfer-based concepts. In this review, we provide an overview of state-of-the-art NanoLuc-based sensors and switches with a focus on the underlying ...
Source: Biochemical Society Transactions - November 26, 2020 Category: Biochemistry Authors: Biewenga L, Rosier BJHM, Merkx M Tags: Biochem Soc Trans Source Type: research

Mechanisms and consequences of dysregulation of the Tiam family of Rac activators in disease.
Abstract The Tiam family proteins - Tiam1 and Tiam2/STEF - are Rac1-specific Guanine Nucleotide Exchange Factors (GEFs) with important functions in epithelial, neuronal, immune and other cell types. Tiam GEFs regulate cellular migration, proliferation and survival, mainly through activating and directing Rac1 signalling. Dysregulation of the Tiam GEFs is significantly associated with human diseases including cancer, immunological and neurological disorders. Uncovering the mechanisms and consequences of dysregulation is therefore imperative to improving the diagnosis and treatment of diseases. Here we compare and c...
Source: Biochemical Society Transactions - November 16, 2020 Category: Biochemistry Authors: Maltas J, Reed H, Porter A, Malliri A Tags: Biochem Soc Trans Source Type: research

Fluorescent proteins for in vivo imaging, where's the biliverdin?
Abstract Noninvasive fluorescent imaging requires far-red and near-infrared fluorescent proteins for deeper imaging. Near-infrared light penetrates biological tissue with blood vessels due to low absorbance, scattering, and reflection of light and has a greater signal-to-noise due to less autofluorescence. Far-red and near-infrared fluorescent proteins absorb light>600 nm to expand the color palette for imaging multiple biosensors and noninvasive in vivo imaging. The ideal fluorescent proteins are bright, photobleach minimally, express well in the desired cells, do not oligomerize, and generate or incorporate...
Source: Biochemical Society Transactions - November 16, 2020 Category: Biochemistry Authors: Montecinos-Franjola F, Lin JY, Rodriguez EA Tags: Biochem Soc Trans Source Type: research

Decoding co-/post-transcriptional complexities of plant transcriptomes and epitranscriptome using next-generation sequencing technologies.
Abstract Next-generation sequencing (NGS) technologies - Illumina RNA-seq, Pacific Biosciences isoform sequencing (PacBio Iso-seq), and Oxford Nanopore direct RNA sequencing (DRS) - have revealed the complexity of plant transcriptomes and their regulation at the co-/post-transcriptional level. Global analysis of mature mRNAs, transcripts from nuclear run-on assays, and nascent chromatin-bound mRNAs using short as well as full-length and single-molecule DRS reads have uncovered potential roles of different forms of RNA polymerase II during the transcription process, and the extent of co-transcriptional pre-mRNA spl...
Source: Biochemical Society Transactions - November 16, 2020 Category: Biochemistry Authors: Reddy ASN, Huang J, Syed NH, Ben-Hur A, Dong S, Gu L Tags: Biochem Soc Trans Source Type: research

'PIPs' in DNA polymerase: PCNA interaction affairs.
Abstract Interaction of PCNA with DNA polymerase is vital to efficient and processive DNA synthesis. PCNA being a homotrimeric ring possesses three hydrophobic pockets mostly involved in an interaction with its binding partners. PCNA interacting proteins contain a short sequence of eight amino acids, popularly coined as PIP motif, which snuggly fits into the hydrophobic pocket of PCNA to stabilize the interaction. In the last two decades, several PIP motifs have been mapped or predicted in eukaryotic DNA polymerases. In this review, we summarize our understandings of DNA polymerase-PCNA interaction, the function o...
Source: Biochemical Society Transactions - November 16, 2020 Category: Biochemistry Authors: Acharya N, Patel SK, Sahu SR, Kumari P Tags: Biochem Soc Trans Source Type: research

Does it take two to tango? RING domain self-association and activity in TRIM E3 ubiquitin ligases.
Abstract TRIM proteins form a protein family that is characterized by a conserved tripartite motif domain comprising a RING domain, one or two B-box domains and a coiled-coil region. Members of this large protein family are important regulators of numerous cellular functions including innate immune responses, transcriptional regulation and apoptosis. Key to their cellular role is their E3 ligase activity which is conferred by the RING domain. Self-association is an important characteristic of TRIM protein activity and is mediated by homodimerization via the coiled-coil region, and in some cases higher order associ...
Source: Biochemical Society Transactions - November 10, 2020 Category: Biochemistry Authors: Fiorentini F, Esposito D, Rittinger K Tags: Biochem Soc Trans Source Type: research

Fuzzy protein theory for disordered proteins.
Abstract Why proteins are fuzzy? Constant adaptation to the cellular environment requires a wide range of changes in protein structure and interactions. Conformational ensembles of disordered proteins in particular exhibit large shifts to activate or inhibit alternative pathways. Fuzziness is critical for liquid-liquid phase separation and conversion of biomolecular condensates into fibrils. Interpretation of these phenomena presents a challenge for the classical structure-function paradigm. Here I discuss a multi-valued formalism, based on fuzzy logic, which can be applied to describe complex cellular behavior of...
Source: Biochemical Society Transactions - November 10, 2020 Category: Biochemistry Authors: Fuxreiter M Tags: Biochem Soc Trans Source Type: research

Membrane protein crystallography in the era of modern structural biology.
Abstract The aim of structural biology has been always the study of biological macromolecules structures and their mechanistic behaviour at molecular level. To achieve its goal, multiple biophysical methods and approaches have become part of the structural biology toolbox. Considered as one of the pillars of structural biology, X-ray crystallography has been the most successful method for solving three-dimensional protein structures at atomic level to date. It is however limited by the success in obtaining well-ordered protein crystals that diffract at high resolution. This is especially true for challenging targe...
Source: Biochemical Society Transactions - November 10, 2020 Category: Biochemistry Authors: Kwan TOC, Axford D, Moraes I Tags: Biochem Soc Trans Source Type: research

Spatio-temporal regulation of gene expression defines subpopulations of epidermal stem cells.
Abstract The search for epidermal stem cells has gained the momentum as they possess unique biological characteristics and a potential in regeneration therapies. Several transcription factors and miRNAs have been identified as epidermal stem cell markers. However, the separation of epidermal stem cells from their progeny remains challenging. The introduction of single-cell transcriptomics pointed to the high degree of heterogeneity in epidermal stem cells imbedded within subpopulations of keratinocytes. Pseudotime inference, RNA velocity, and cellular entropy further enhanced our knowledge of stem cells, allowing ...
Source: Biochemical Society Transactions - November 10, 2020 Category: Biochemistry Authors: Aruketty M, Kurinna S Tags: Biochem Soc Trans Source Type: research

The complexity of PRC2 catalysts CLF and SWN in plants.
Abstract Polycomb repressive complex 2 (PRC2) is an evolutionally conserved multisubunit complex essential for the development of eukaryotes. In Arabidopsis thaliana (Arabidopsis), CURLY LEAF (CLF) and SWINGER (SWN) are PRC2 catalytic subunits that repress gene expression through trimethylating histone H3 at lysine 27 (H3K27me3). CLF and SWN function to safeguard the appropriate expression of key developmental regulators throughout the plant life cycle. Recent researches have advanced our knowledge of the biological roles and the regulation of the activity of CLF and SWN. In this review, we summarize these recent ...
Source: Biochemical Society Transactions - November 10, 2020 Category: Biochemistry Authors: Shu J, Chen C, Li C, Cui Y Tags: Biochem Soc Trans Source Type: research

Serological antibody testing in the COVID-19 pandemic: their molecular basis and applications.
Abstract The ongoing COVID-19 pandemic has placed an overwhelming burden on the healthcare system, and caused major disruption to the world economy. COVID-19 is caused by SARS-CoV-2, a novel coronavirus that leads to a variety of symptoms in humans, including cough, fever and respiratory failure. SARS-CoV-2 infection can trigger extensive immune responses, including the production of antibodies. The detection of antibody response by serological testing provides a supplementary diagnostic tool to molecular tests. We hereby present a succinct yet comprehensive review on the antibody response to SARS-CoV-2 infection,...
Source: Biochemical Society Transactions - November 10, 2020 Category: Biochemistry Authors: Jiang JC, Zhang Y Tags: Biochem Soc Trans Source Type: research

From protocells to prototissues: a materials chemistry approach.
Abstract Prototissues comprise free-standing 3D networks of interconnected protocell consortia that communicate and display synergistic functions. Significantly, they can be constructed from functional molecules and materials, providing unprecedented opportunities to design tissue-like architectures that can do more than simply mimic living tissues. They could function under extreme conditions and exhibit a wide range of mechanical properties and bio-inspired metabolic functions. In this perspective, I will start by describing recent advancements in the design and synthetic construction of prototissues. I will the...
Source: Biochemical Society Transactions - November 6, 2020 Category: Biochemistry Authors: Gobbo P Tags: Biochem Soc Trans Source Type: research

Exploiting teeth as a model to study basic features of signaling pathways.
Abstract Teeth constitute a classical model for the study of signaling pathways and their roles in mediating interactions between cells and tissues in organ development, homeostasis and regeneration. Rodent teeth are mostly used as experimental models. Rodent molars have proved fundamental in the study of epithelial-mesenchymal interactions and embryonic organ morphogenesis, as well as to faithfully model human diseases affecting dental tissues. The continuously growing rodent incisor is an excellent tool for the investigation of the mechanisms regulating stem cells dynamics in homeostasis and regeneration. In thi...
Source: Biochemical Society Transactions - November 6, 2020 Category: Biochemistry Authors: Pagella P, Porcheri C, Mitsiadis TA Tags: Biochem Soc Trans Source Type: research

Mitochondrial DNA in innate immune responses against infectious diseases.
Abstract Mitochondrial DNA (mtDNA) can initiate an innate immune response when mislocalized in a compartment other than the mitochondrial matrix. mtDNA plays significant roles in regulating mitochondrial dynamics as well as mitochondrial unfolded protein response (UPR). The mislocalized extra-mtDNA can elicit innate immune response via cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, inducing the expression of the interferon-stimulated genes (ISGs). Also, cytosolic damaged mtDNA is cleared up by various pathways which are responsible for participating in the activation of inflammatory r...
Source: Biochemical Society Transactions - November 6, 2020 Category: Biochemistry Authors: Das P, Chakrabarti O Tags: Biochem Soc Trans Source Type: research

Intrinsically disordered proteins and membranes: a marriage of convenience for cell signalling?
Abstract The structure-function paradigm has guided investigations into the molecules involved in cellular signalling for decades. The peripheries of this paradigm, however, start to unravel when considering the co-operation between proteins and the membrane in signalling processes. Intrinsically disordered regions hold distinct advantages over folded domains in terms of their binding promiscuity, sensitivity to their particular environment and their ease of modulation through post-translational modifications. Low sequence complexity and bias towards charged residues are also favourable for the multivalent electro...
Source: Biochemical Society Transactions - November 6, 2020 Category: Biochemistry Authors: Cornish J, Chamberlain SG, Owen D, Mott HR Tags: Biochem Soc Trans Source Type: research

The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants.
Abstract The extracellular matrix (ECM) dynamics in tumour tissue are deregulated compared to the ECM in healthy tissue along with disorganized architecture and irregular behaviour of the residing cells. Nitric oxide (NO) as a pleiotropic molecule exerts different effects on the components of the ECM driving or inhibiting augmented angiogenesis and tumour progression and tumour cell proliferation and metastasis. These effects rely on the concentration of NO within the tumour tissue, the nature of the surrounding microenvironment and the sensitivity of resident cells to NO. In this review article, we summarize the ...
Source: Biochemical Society Transactions - November 5, 2020 Category: Biochemistry Authors: Alsharabasy AM, Glynn SA, Pandit A Tags: Biochem Soc Trans Source Type: research

Extracellular vesicles and the extracellular matrix: a new paradigm or old news?
Abstract Extracellular vesicles (EV) are implicated in a variety of functions affecting the extracellular matrix (ECM), including matrix degradation, cross-linking of matrix proteins and matrix calcification. These processes are important in many physiological contexts such as angiogenesis and wound healing, and dysregulation of ECM homeostasis contributes to a wide range of diseases including fibrosis, cancer and arthritis. Most studies of EV have focussed on their roles in cell:cell communication, but EV can exist as integral components of the ECM. By far the most well-characterised ECM-resident EV are matrix ve...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Lewin S, Hunt S, Lambert DW Tags: Biochem Soc Trans Source Type: research

Unveiling the cryo-EM structure of retromer.
Abstract Retromer (VPS26/VPS35/VPS29) is a highly conserved eukaryotic protein complex that localizes to endosomes to sort transmembrane protein cargoes into vesicles and elongated tubules. Retromer mediates retrieval pathways from endosomes to the trans-Golgi network in all eukaryotes and further facilitates recycling pathways to the plasma membrane in metazoans. In cells, retromer engages multiple partners to orchestrate the formation of tubulovesicular structures, including sorting nexin (SNX) proteins, cargo adaptors, GTPases, regulators, and actin remodeling proteins. Retromer-mediated pathways are especially...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Chandra M, Kendall AK, Jackson LP Tags: Biochem Soc Trans Source Type: research

Emerging aspects in the regulation of ferroptosis.
Abstract Lipid peroxidation has been associated with a wide array of (patho)physiological conditions. Remarkably, in the last few years, a novel cell death modality termed ferroptosis was recognized as a process initiated by iron-dependent oxidation of lipids. The sensitivity to ferroptosis is determined by the activity of antioxidant systems working on the repair of oxidized phospholipids and also metabolic pathways controlling the availability of substrates susceptible to lipid peroxidation. Non-enzymatic antioxidants such as vitamin E, which has long been acknowledged as an efficient inhibitor of lipid peroxida...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Nehring H, Meierjohann S, Friedmann Angeli JP Tags: Biochem Soc Trans Source Type: research

RAS GTPase signalling to alternative effector pathways.
Abstract RAS GTPases are fundamental regulators of development and drivers of an extraordinary number of human cancers. RAS oncoproteins constitutively signal through downstream effector proteins, triggering cancer initiation, progression and metastasis. In the absence of targeted therapeutics to mutant RAS itself, inhibitors of downstream pathways controlled by the effector kinases RAF and PI3K have become tools in the treatment of RAS-driven tumours. Unfortunately, the efficacy of this approach has been greatly minimized by the prevalence of acquired drug resistance. Decades of research have established that RAS...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Singh S, Smith MJ Tags: Biochem Soc Trans Source Type: research

Protein phosphatase-1: dual activity regulation by Inhibitor-2.
Abstract Inhibitor-2 (I2) ranks amongst the most ancient regulators of protein phosphatase-1 (PP1). It is a small, intrinsically disordered protein that was originally discovered as a potent inhibitor of PP1. However, later investigations also characterized I2 as an activator of PP1 as well as a chaperone for PP1 folding. Numerous studies disclosed the importance of I2 for diverse cellular processes but did not describe a unifying molecular principle of PP1 regulation. We have re-analyzed the literature on I2 in the light of current insights of PP1 structure and regulation. Extensive biochemical data, largely igno...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Lemaire S, Bollen M Tags: Biochem Soc Trans Source Type: research

Biosynthesis of lanthionine-constrained agonists of G protein-coupled receptors.
Abstract The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as hydrogen bridges or is induced by ligand-receptor interactions. The conformational freedom of a peptide can be constrained by intramolecular cross-links. Conformational constraints enhance the receptor specificity, may lead to biased activity and confer proteolytic resistance to peptidic GPCR agonists. Chemical synthesis allows to introduce a variety of cross-links into a peptide and is suitable for bulk production of relatively simple lead pe...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Moll GN, Kuipers A, Rink R, Bosma T, de Vries L, Namsolleck P Tags: Biochem Soc Trans Source Type: research

Effects of carboxyl-terminal methylation on holoenzyme function of the PP2A subfamily.
Abstract Phosphoprotein Phosphatases (PPPs) are enzymes highly conserved from yeast and human and catalyze the majority of the serine and threonine dephosphorylation in cells. To achieve substrate specificity and selectivity, PPPs form multimeric holoenzymes consisting of catalytic, structural/scaffolding, and regulatory subunits. For the Protein Phosphatase 2A (PP2A)-subfamily of PPPs, holoenzyme assembly is at least in part regulated by an unusual carboxyl-terminal methyl-esterification, commonly referred to as 'methylation'. Carboxyl-terminal methylation is catalyzed by Leucine carboxyl methyltransferase-1 (LCM...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Nasa I, Kettenbach AN Tags: Biochem Soc Trans Source Type: research

Function and regulation of corin in physiology and disease.
Abstract Atrial natriuretic peptide (ANP) is of major importance in the maintenance of electrolyte balance and normal blood pressure. Reduced plasma ANP levels are associated with the increased risk of cardiovascular disease. Corin is a type II transmembrane serine protease that converts the ANP precursor to mature ANP. Corin deficiency prevents ANP generation and alters electrolyte and body fluid homeostasis. Corin is synthesized as a zymogen that is proteolytically activated on the cell surface. Factors that disrupt corin folding, intracellular trafficking, cell surface expression, and zymogen activation are exp...
Source: Biochemical Society Transactions - October 30, 2020 Category: Biochemistry Authors: Dong N, Niu Y, Chen Y, Sun S, Wu Q Tags: Biochem Soc Trans Source Type: research

The miR-21 potential of serving as a biomarker for liver diseases in clinical practice.
Abstract The role of miR-21 in the pathogenesis of various liver diseases, together with the possibility of detecting microRNA in the circulation, makes miR-21 a potential biomarker for noninvasive detection. In this review, we summarize the potential utility of extracellular miR-21 in the clinical management of hepatic disease patients and compared it with the current clinical practice. MiR-21 shows screening and prognostic value for liver cancer. In liver cirrhosis, miR-21 may serve as a biomarker for the differentiating diagnosis and prognosis. MiR-21 is also a potential biomarker for the severity of hepatitis....
Source: Biochemical Society Transactions - October 29, 2020 Category: Biochemistry Authors: Zhang J, Li D, Zhang R, Gao P, Peng R, Li J Tags: Biochem Soc Trans Source Type: research

ER functions are exploited by viruses to support distinct stages of their life cycle.
Abstract The endoplasmic reticulum (ER), with its expansive membranous system and a vast network of chaperones, enzymes, sensors, and ion channels, orchestrates diverse cellular functions, ranging from protein synthesis, folding, secretion, and degradation to lipid biogenesis and calcium homeostasis. Strikingly, some of the functions of the ER are exploited by viruses to promote their life cycles. During entry, viruses must penetrate a host membrane and reach an intracellular destination to express and replicate their genomes. These events lead to the assembly of new viral progenies that exit the host cell, thereb...
Source: Biochemical Society Transactions - October 29, 2020 Category: Biochemistry Authors: Chen YJ, Bagchi P, Tsai B Tags: Biochem Soc Trans Source Type: research

The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia.
Abstract Heterotetrameric adaptor protein (AP) complexes play key roles in protein sorting and transport vesicle formation in the endomembrane system of eukaryotic cells. One of these complexes, AP-4, was identified over 20 years ago but, up until recently, its function remained unclear. AP-4 associates with the trans-Golgi network (TGN) through interaction with small GTPases of the ARF family and recognizes transmembrane proteins (i.e. cargos) having specific sorting signals in their cytosolic domains. Recent studies identified accessory proteins (tepsin, RUSC2 and the FHF complex) that co-operate with AP-4, and ...
Source: Biochemical Society Transactions - October 21, 2020 Category: Biochemistry Authors: Mattera R, De Pace R, Bonifacino JS Tags: Biochem Soc Trans Source Type: research

Transmission and prevention of SARS-CoV-2.
This article mainly focuses on published studies on the transmission routes of SARS-CoV-2 including contact transmission, droplet transmission, aerosol transmission and fecal-oral transmission, as well as related research approaches, such as epidemiological investigations, environmental sampling in hospitals and laboratories and animal models. We also provide four specific recommendations for the prevention and control of SARS-CoV-2 that may help reduce the risk of SARS-CoV-2 infection under different environmental conditions. First, social distancing, rational use of face masks and respirators, eye protection, and hand di...
Source: Biochemical Society Transactions - October 21, 2020 Category: Biochemistry Authors: Wang Z, Fu Y, Guo Z, Li J, Li J, Cheng H, Lu B, Sun Q Tags: Biochem Soc Trans Source Type: research

Emerging roles of lamins and DNA damage repair mechanisms in ovarian cancer.
Abstract Lamins are type V intermediate filament proteins which are ubiquitously present in all metazoan cells providing a platform for binding of chromatin and related proteins, thereby serving a wide range of nuclear functions including DNA damage repair. Altered expression of lamins in different subtypes of cancer is evident from researches worldwide. But whether cancer is a consequence of this change or this change is a consequence of cancer is a matter of future investigation. However changes in the expression levels of lamins is reported to have direct or indirect association with cancer progression or have ...
Source: Biochemical Society Transactions - October 21, 2020 Category: Biochemistry Authors: Sengupta D, Mukhopadhyay A, Sengupta K Tags: Biochem Soc Trans Source Type: research

A 'tad' of hope in the fight against airway disease.
Abstract Xenopus tadpoles have emerged as a powerful in vivo model system to study mucociliary epithelia such as those found in the human airways. The tadpole skin has mucin-secreting cells, motile multi-ciliated cells, ionocytes (control local ionic homeostasis) and basal stem cells. This cellular architecture is very similar to the large airways of the human lungs and represents an easily accessible and experimentally tractable model system to explore the molecular details of mucociliary epithelia. Each of the cell types in the tadpole skin has a human equivalent and a conserved network of genes and signalling p...
Source: Biochemical Society Transactions - October 20, 2020 Category: Biochemistry Authors: Dubaissi E Tags: Biochem Soc Trans Source Type: research

Engineered protein switches for exogenous control of gene expression.
Abstract There is an ongoing need in the synthetic biology community for novel ways to regulate gene expression. Protein switches, which sense biological inputs and respond with functional outputs, represent one way to meet this need. Despite the fact that there is already a large pool of transcription factors and signaling proteins available, the pool of existing switches lacks the substrate specificities and activities required for certain applications. Therefore, a large number of techniques have been applied to engineer switches with novel properties. Here we discuss some of these techniques by broadly organiz...
Source: Biochemical Society Transactions - October 20, 2020 Category: Biochemistry Authors: Spisak S, Ostermeier M Tags: Biochem Soc Trans Source Type: research

Allosteric inhibition of LRRK2, where are we now.
Abstract Parkinson's disease (PD) is the second most common neurodegenerative disease. In recent years, it has been shown that leucine-rich repeat kinase 2 (LRRK2) has a crucial function in both familial and sporadic forms of PD. LRRK2 pathogenic mutations are thought to result in an increase in LRRK2 kinase activity. Thus, inhibiting LRRK2 kinase activity has become a main therapeutic target. Many compounds capable of inhibiting LRRK2 kinase activity with high selectivity and brain availability have been described. However, the safety of long-term use of these ATP-competitive LRRK2 kinase inhibitors has been chal...
Source: Biochemical Society Transactions - October 20, 2020 Category: Biochemistry Authors: Soliman A, Cankara FN, Kortholt A Tags: Biochem Soc Trans Source Type: research

Emerging mass spectrometry-based proteomics methodologies for novel biomedical applications.
Abstract Research into the basic biology of human health and disease, as well as translational human research and clinical applications, all benefit from the growing accessibility and versatility of mass spectrometry (MS)-based proteomics. Although once limited in throughput and sensitivity, proteomic studies have quickly grown in scope and scale over the last decade due to significant advances in instrumentation, computational approaches, and bio-sample preparation. Here, we review these latest developments in MS and highlight how these techniques are used to study the mechanisms, diagnosis, and treatment of huma...
Source: Biochemical Society Transactions - October 20, 2020 Category: Biochemistry Authors: Pino LK, Rose J, O'Broin A, Shah S, Schilling B Tags: Biochem Soc Trans Source Type: research

Trehalose 6-phosphate signalling and impact on crop yield.
Abstract The domestication and breeding of crops has been a major achievement for mankind enabling the development of stable societies and civilisation. Crops have become more productive per unit area of cultivated land over the course of domestication supporting a current global population of 7.8 billion. Food security crops such as wheat and maize have seen large changes compared with early progenitors. Amongst processes that have been altered in these crops, is the allocation of carbon resources to support larger grain yield (grain number and size). In wheat, reduction in stem height has enabled diversion of re...
Source: Biochemical Society Transactions - October 1, 2020 Category: Biochemistry Authors: Paul MJ, Watson A, Griffiths CA Tags: Biochem Soc Trans Source Type: research

Studying the surfaces of bacteria using neutron scattering: finding new openings for antibiotics.
Abstract The use of neutrons as a scattering probe to investigate biological membranes has steadily grown in the past three decades, shedding light on the structure and behaviour of this ubiquitous and fundamental biological barrier. Meanwhile, the rise of antibiotic resistance has catalysed a renewed interest in understanding the mechanisms underlying the dynamics of antibiotics interaction with the bacterial cell envelope. It is widely recognised that the key reason behind the remarkable success of Gram-negative pathogens in developing antibiotic resistance lies in the effectiveness of their outer membrane (OM) ...
Source: Biochemical Society Transactions - October 1, 2020 Category: Biochemistry Authors: Paracini N, Clifton LA, Lakey JH Tags: Biochem Soc Trans Source Type: research

Condensin complexes: understanding loop extrusion one conformational change at a time.
Abstract Condensin and cohesin, both members of the structural maintenance of chromosome (SMC) family, contribute to the regulation and structure of chromatin. Recent work has shown both condensin and cohesin extrude DNA loops and most likely work via a conserved mechanism. This review focuses on condensin complexes, highlighting recent in vitro work characterising DNA loop formation and protein structure. We discuss similarities between condensin and cohesin complexes to derive a possible mechanistic model, as well as discuss differences that exist between the different condensin isoforms found in higher eukaryot...
Source: Biochemical Society Transactions - October 1, 2020 Category: Biochemistry Authors: Cutts EE, Vannini A Tags: Biochem Soc Trans Source Type: research

Human 2-oxoglutarate-dependent oxygenases: nutrient sensors, stress responders, and disease mediators.
Abstract Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases are a conserved enzyme class that catalyse diverse oxidative reactions across nature. In humans, these enzymes hydroxylate a broad range of biological substrates including DNA, RNA, proteins and some metabolic intermediates. Correspondingly, members of the 2OG-dependent oxygenase superfamily have been linked to fundamental biological processes, and found dysregulated in numerous human diseases. Such findings have stimulated efforts to understand both the biochemical activities and cellular functions of these enzymes, as many have been poorly studied. In thi...
Source: Biochemical Society Transactions - September 27, 2020 Category: Biochemistry Authors: Fletcher SC, Coleman ML Tags: Biochem Soc Trans Source Type: research

Whence Blobs? Phylogenetics of functional protein condensates.
es AM Abstract What do we know about the molecular evolution of functional protein condensation? The capacity of proteins to form biomolecular condensates (compact, protein-rich states, not bound by membranes, but still separated from the rest of the contents of the cell) appears in many cases to be bestowed by weak, transient interactions within one or between proteins. Natural selection is expected to remove or fix amino acid changes, insertions or deletions that preserve and change this condensation capacity when doing so is beneficial to the cell. A few recent studies have begun to explore this frontier of phy...
Source: Biochemical Society Transactions - September 27, 2020 Category: Biochemistry Authors: Pritišanac I, Zarin T, Forman-Kay JD, Moses AM Tags: Biochem Soc Trans Source Type: research

Splitting up to heal: mitochondrial shape regulates signaling for focal membrane repair.
Abstract Mitochondria are central to the health of eukaryotic cells. While commonly known for their bioenergetic role, mitochondria also function as signaling organelles that regulate cell stress responses capable of restoring homeostasis or leading the stressed cell to eventual death. Damage to the plasma membrane is a potentially fatal stressor incurred by all cells. Repairing plasma membrane damage requires cells to mount a rapid and localized response to injury. Accumulating evidence has identified a role for mitochondria as an important facilitator of this acute and localized repair response. However, as mito...
Source: Biochemical Society Transactions - September 27, 2020 Category: Biochemistry Authors: Horn A, Jaiswal JK Tags: Biochem Soc Trans Source Type: research

CRISPR-based gene expression control for synthetic gene circuits.
Abstract Synthetic gene circuits allow us to govern cell behavior in a programmable manner, which is central to almost any application aiming to harness engineered living cells for user-defined tasks. Transcription factors (TFs) constitute the 'classic' tool for synthetic circuit construction but some of their inherent constraints, such as insufficient modularity, orthogonality and programmability, limit progress in such forward-engineering endeavors. Here we review how CRISPR (clustered regularly interspaced short palindromic repeats) technology offers new and powerful possibilities for synthetic circuit design. ...
Source: Biochemical Society Transactions - September 22, 2020 Category: Biochemistry Authors: Santos-Moreno J, Schaerli Y Tags: Biochem Soc Trans Source Type: research

Smc5/6, an atypical SMC complex with two RING-type subunits.
ell J Abstract The Smc5/6 complex plays essential roles in chromosome segregation and repair, by promoting disjunction of sister chromatids. The core of the complex is constituted by an heterodimer of Structural Maintenance of Chromosomes (SMC) proteins that use ATP hydrolysis to dynamically associate with and organize chromosomes. In addition, the Smc5/6 complex contains six non-SMC subunits. Remarkably, and differently to other SMC complexes, the Nse1 and Nse2 subunits contain RING-type domains typically found in E3 ligases, pointing to the capacity to regulate other proteins and complexes through ubiquitin-like...
Source: Biochemical Society Transactions - September 22, 2020 Category: Biochemistry Authors: Solé-Soler R, Torres-Rosell J Tags: Biochem Soc Trans Source Type: research

A review of methods for the reconstruction and analysis of integrated genome-scale models of metabolism and regulation.
Abstract The current survey aims to describe the main methodologies for extending the reconstruction and analysis of genome-scale metabolic models and phenotype simulation with Flux Balance Analysis mathematical frameworks, via the integration of Transcriptional Regulatory Networks and/or gene expression data. Although the surveyed methods are aimed at improving phenotype simulations obtained from these models, the perspective of reconstructing integrated genome-scale models of metabolism and gene expression for diverse prokaryotes is still an open challenge. PMID: 32940659 [PubMed - as supplied by publisher]...
Source: Biochemical Society Transactions - September 16, 2020 Category: Biochemistry Authors: Cruz F, Faria JP, Rocha M, Rocha I, Dias O Tags: Biochem Soc Trans Source Type: research

Review on material parameters to enhance bone cell function in vitro and in vivo.
Abstract Bone plays critical roles in support, protection, movement, and metabolism. Although bone has an innate capacity for regeneration, this capacity is limited, and many bone injuries and diseases require intervention. Biomaterials are a critical component of many treatments to restore bone function and include non-resorbable implants to augment bone and resorbable materials to guide regeneration. Biomaterials can vary considerably in their biocompatibility and bioactivity, which are functions of specific material parameters. The success of biomaterials in bone augmentation and regeneration is based on their ...
Source: Biochemical Society Transactions - September 16, 2020 Category: Biochemistry Authors: Madsen E, Mededovic M, Kohn DH Tags: Biochem Soc Trans Source Type: research

The tryptophan biosynthetic pathway is essential for Mycobacterium tuberculosis to cause disease.
Abstract Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is the most significant cause of death from a single infectious agent worldwide. Antibiotic-resistant strains of M. tuberculosis represent a threat to effective treatment, and the long duration, toxicity and complexity of current chemotherapy for antibiotic-resistant disease presents a need for new therapeutic approaches with novel modes of action. M. tuberculosis is an intracellular pathogen that must survive phagocytosis by macrophages, dendritic cells or neutrophils to establish an infection. The tryptophan biosynthetic pathway is re...
Source: Biochemical Society Transactions - September 10, 2020 Category: Biochemistry Authors: Lott JS Tags: Biochem Soc Trans Source Type: research

Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for ….
Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for…. Biochem Soc Trans. 2020 Sep 11;: Authors: Cook SJ, Tucker JA, Lochhead PA Abstract ERK5 is a protein kinase that also contains a nuclear localisation signal and a transcriptional transactivation domain. Inhibition of ERK5 has therapeutic potential in cancer and inflammation and this has prompted the development of ERK5 kinase inhibitors (ERK5i). However, few ERK5i programmes have taken account of the ERK5 transactivation domain. We have recently shown that the binding of small molecule E...
Source: Biochemical Society Transactions - September 10, 2020 Category: Biochemistry Authors: Cook SJ, Tucker JA, Lochhead PA Tags: Biochem Soc Trans Source Type: research

To be more precise: the role of intracellular trafficking in development and pattern formation.
Abstract Living cells interpret a variety of signals in different contexts to elucidate functional responses. While the understanding of signalling molecules, their respective receptors and response at the gene transcription level have been relatively well-explored, how exactly does a single cell interpret a plethora of time-varying signals? Furthermore, how their subsequent responses at the single cell level manifest in the larger context of a developing tissue is unknown. At the same time, the biophysics and chemistry of how receptors are trafficked through the complex dynamic transport network between the plasm...
Source: Biochemical Society Transactions - September 10, 2020 Category: Biochemistry Authors: York HM, Coyle J, Arumugam S Tags: Biochem Soc Trans Source Type: research