Promotion of cancer cell stemness by Ras.
Abstract Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependen...
Source: Biochemical Society Transactions - February 5, 2021 Category: Biochemistry Authors: Chippalkatti R, Abankwa D Tags: Biochem Soc Trans Source Type: research

Advances in modelling the human microbiome-gut-brain axis in vitro.
Abstract The human gut microbiome has emerged as a key player in the bidirectional communication of the gut-brain axis, affecting various aspects of homeostasis and pathophysiology. Until recently, the majority of studies that seek to explore the mechanisms underlying the microbiome-gut-brain axis cross-talk, relied almost exclusively on animal models, and particularly gnotobiotic mice. Despite the great progress made with these models, various limitations, including ethical considerations and interspecies differences that limit the translatability of data to human systems, pushed researchers to seek for alternati...
Source: Biochemical Society Transactions - February 5, 2021 Category: Biochemistry Authors: Moysidou CM, Owens RM Tags: Biochem Soc Trans Source Type: research

The ERK mitogen-activated protein kinase signaling network: the final frontier in RAS signal transduction.
Abstract The RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic developmental disorders. This protein kinase cascade is one of the most intensely studied cellular signaling networks and has been frequently targeted by the pharmaceutical industry, with more than 30 inhibitors either approved or under clinical evaluation. The ERK-MAPK cascade was originally depicted as a serial and linear, unidirectional pathway that relays extracellular signals, such as mitogenic stimuli, through the cytoplasm to the nucleus. Howev...
Source: Biochemical Society Transactions - February 5, 2021 Category: Biochemistry Authors: Klomp JE, Klomp JA, Der CJ Tags: Biochem Soc Trans Source Type: research

Computational investigations of allostery in aromatic amino acid biosynthetic enzymes.
Abstract Allostery, in which binding of ligands to remote sites causes a functional change in the active sites, is a fascinating phenomenon observed in enzymes. Allostery can occur either with or without significant conformational changes in the enzymes, and the molecular basis of its mechanism can be difficult to decipher using only experimental techniques. Computational tools for analyzing enzyme sequences, structures, and dynamics can provide insights into the allosteric mechanism at the atomic level. Combining computational and experimental methods offers a powerful strategy for the study of enzyme allostery. ...
Source: Biochemical Society Transactions - February 5, 2021 Category: Biochemistry Authors: Jiao W Tags: Biochem Soc Trans Source Type: research

Rhizobia: highways to NO.
Meilhoc E Abstract The interaction between rhizobia and their legume host plants conduces to the formation of specialized root organs called nodules where rhizobia differentiate into bacteroids which fix atmospheric nitrogen to the benefit of the plant. This beneficial symbiosis is of importance in the context of sustainable agriculture as legumes do not require the addition of nitrogen fertilizer to grow. Interestingly, nitric oxide (NO) has been detected at various steps of the rhizobium-legume symbiosis where it has been shown to play multifaceted roles. Both bacterial and plant partners are involved in NO synt...
Source: Biochemical Society Transactions - February 5, 2021 Category: Biochemistry Authors: Ruiz B, Frostegård Å, Bruand C, Meilhoc E Tags: Biochem Soc Trans Source Type: research

Finding new edges: systems approaches to MTOR signaling.
eck K Abstract Cells have evolved highly intertwined kinase networks to finely tune cellular homeostasis to the environment. The network converging on the mechanistic target of rapamycin (MTOR) kinase constitutes a central hub that integrates metabolic signals and adapts cellular metabolism and functions to nutritional changes and stress. Feedforward and feedback loops, crosstalks and a plethora of modulators finely balance MTOR-driven anabolic and catabolic processes. This complexity renders it difficult - if not impossible - to intuitively decipher signaling dynamics and network topology. Over the last two decad...
Source: Biochemical Society Transactions - February 5, 2021 Category: Biochemistry Authors: Heberle AM, Rehbein U, Rodríguez Peiris M, Thedieck K Tags: Biochem Soc Trans Source Type: research

Recent insight into the role of RING-finger E3 ligases in glioma.
Abstract The ubiquitin proteasome system (UPS) serves as the major posttranslational modification system for the maintenance of protein homeostasis. The ubiquitin ligases (E3s) are responsible for the recognition and recruitment of specific substrate proteins for polyubiquitination. Really interesting new gene (RING) finger E3s account for the majority of E3s. The human genome encodes more than 600 RING E3s, which are divided into three subclasses: single polypeptide E3s, cullin-RING ligases (CRLs) and other multisubunit E3s. The abnormal regulation of RING E3s has been reported to disrupt normal biological proces...
Source: Biochemical Society Transactions - February 5, 2021 Category: Biochemistry Authors: Cao Y, Zhou H, Chen X, Li Y, Hu J, Zhou G, Wang L Tags: Biochem Soc Trans Source Type: research

Endothelial response to glucose: dysfunction, metabolism, and transport.
Abstract The endothelial cell response to glucose plays an important role in both health and disease. Endothelial glucose-induced dysfunction was first studied in diabetic animal models and in cells cultured in hyperglycemia. Four classical dysfunction pathways were identified, which were later shown to result from the common mechanism of mitochondrial superoxide overproduction. More recently, non-coding RNA, extracellular vesicles, and sodium-glucose cotransporter-2 inhibitors were shown to affect glucose-induced endothelial dysfunction. Endothelial cells also metabolize glucose for their own energetic needs. Res...
Source: Biochemical Society Transactions - February 1, 2021 Category: Biochemistry Authors: Clyne AM Tags: Biochem Soc Trans Source Type: research

The structure and function of protein kinase C-related kinases (PRKs).
Abstract The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, but while PRK1 is relatively well-characterized, the entire PRK family remains understudied. Here, we provide a holistic overview of the structure and function of PRKs and describe the molecular events that govern activation and autoregulation of catalytic activity, including phosphorylation, protein interactions and lipid binding. We begin with a structura...
Source: Biochemical Society Transactions - February 1, 2021 Category: Biochemistry Authors: Sophocleous G, Owen D, Mott HR Tags: Biochem Soc Trans Source Type: research

Mechanistic insights into KDM4A driven genomic instability.
Abstract Alterations in global epigenetic signatures on chromatin are well established to contribute to tumor initiation and progression. Chromatin methylation status modulates several key cellular processes that maintain the integrity of the genome. KDM4A, a demethylase that belongs to the Fe-II dependent dioxygenase family that uses α-ketoglutarate and molecular oxygen as cofactors, is overexpressed in several cancers and is associated with an overall poor prognosis. KDM4A demethylates lysine 9 (H3K9me2/3) and lysine 36 (H3K36me3) methyl marks on histone H3. Given the complexity that exists with these mark...
Source: Biochemical Society Transactions - January 25, 2021 Category: Biochemistry Authors: Young NL, Dere R Tags: Biochem Soc Trans Source Type: research

A mass spectrometry-based glycotope-centric cellular glycomics is the more fruitful way forward to see the forest for the trees.
Abstract The nature of protein glycosylation renders cellular glycomics a very challenging task in having to deal with all the disparate glycans carried on membrane glycoproteins. Rapid mapping by mass spectrometry analysis provides only a coarse sketch of the glycomic complexity based primarily on glycosyl compositions, whereby the missing high-resolution structural details require a combination of multi-mode separations and multi-stages of induced fragmentation to gain sufficiently discriminative precision, often at the expenses of throughput and sensitivity. Given the available technology and foreseeable advanc...
Source: Biochemical Society Transactions - January 25, 2021 Category: Biochemistry Authors: Khoo KH Tags: Biochem Soc Trans Source Type: research

The search for RNA-binding proteins: a technical and interdisciplinary challenge.
Abstract RNA-binding proteins are customarily regarded as important facilitators of gene expression. In recent years, RNA-protein interactions have also emerged as a pervasive force in the regulation of homeostasis. The compendium of proteins with provable RNA-binding function has swelled from the hundreds to the thousands astride the partnership of mass spectrometry-based proteomics and RNA sequencing. At the foundation of these advances is the adaptation of RNA-centric capture methods that can extract bound protein that has been cross-linked in its native environment. These methods reveal snapshots in time displ...
Source: Biochemical Society Transactions - January 25, 2021 Category: Biochemistry Authors: Smith JM, Sandow JJ, Webb AI Tags: Biochem Soc Trans Source Type: research

Environment-coupled models of leaf metabolism.
r N Abstract The plant leaf is the main site of photosynthesis. This process converts light energy and inorganic nutrients into chemical energy and organic building blocks for the biosynthesis and maintenance of cellular components and to support the growth of the rest of the plant. The leaf is also the site of gas-water exchange and due to its large surface, it is particularly vulnerable to pathogen attacks. Therefore, the leaf's performance and metabolic modes are inherently determined by its interaction with the environment. Mathematical models of plant metabolism have been successfully applied to study various...
Source: Biochemical Society Transactions - January 25, 2021 Category: Biochemistry Authors: Töpfer N Tags: Biochem Soc Trans Source Type: research

Pore-forming toxins in infection and immunity.
Abstract The integrity of the plasma membranes is extremely crucial for the survival and proper functioning of the cells. Organisms from all kingdoms of life employ specialized pore-forming proteins and toxins (PFPs and PFTs) that perforate cell membranes, and cause detrimental effects. PFPs/PFTs exert their damaging actions by forming oligomeric pores in the membrane lipid bilayer. PFPs/PFTs play important roles in diverse biological processes. Many pathogenic bacteria secrete PFTs for executing their virulence mechanisms. The immune system of the higher vertebrates employs PFPs to kill pathogen-infected cells an...
Source: Biochemical Society Transactions - January 25, 2021 Category: Biochemistry Authors: Verma P, Gandhi S, Lata K, Chattopadhyay K Tags: Biochem Soc Trans Source Type: research

Lytic polysaccharide monooxygenases and other histidine-brace copper proteins: structure, oxygen activation and biotechnological applications.
Johansen KS Abstract Lytic polysaccharide monooxygenases (LPMOs) are mononuclear copper enzymes that catalyse the oxidative cleavage of glycosidic bonds. They are characterised by two histidine residues that coordinate copper in a configuration termed the Cu-histidine brace. Although first identified in bacteria and fungi, LPMOs have since been found in all biological kingdoms. LPMOs are now included in commercial enzyme cocktails used in industrial biorefineries. This has led to increased process yield due to the synergistic action of LPMOs with glycoside hydrolases. However, the introduction of LPMOs makes contr...
Source: Biochemical Society Transactions - January 15, 2021 Category: Biochemistry Authors: Ipsen JØ, Hallas-Møller M, Brander S, Lo Leggio L, Johansen KS Tags: Biochem Soc Trans Source Type: research

CRISPR base editing applications for identifying cancer-driving mutations.
Abstract CRISPR base editing technology is a promising genome editing tool as (i) it does not require a DNA template to introduce mutations and (ii) it avoids creating DNA double-strand breaks, which can lead to unintended chromosomal alterations or elicit an unwanted DNA damage response. Given many cancers originate from point mutations in cancer-driving genes, the application of base editing for either modelling tumour development, therapeutic editing, or functional screening is of great promise. In this review, we summarise current DNA base editing technologies and will discuss recent advancements and existing ...
Source: Biochemical Society Transactions - January 15, 2021 Category: Biochemistry Authors: Pal M, Herold MJ Tags: Biochem Soc Trans Source Type: research

Understanding the immune responses involved in mediating protection or immunopathology during leishmaniasis.
Abstract Leishmaniasis is a vector-borne Neglected Tropical Disease (NTD) transmitted by the sand fly and is a major public health problem worldwide. Infections caused by Leishmania clinically manifest as a wide range of diseases, such as cutaneous (CL), diffuse cutaneous (DCL), mucosal (MCL) and visceral leishmaniasis (VL). The host innate and adaptative immune responses play critical roles in the defense against leishmaniasis. However, Leishmania parasites also manipulate the host immune response for their survival and replication. In addition, other factors such as sand fly salivary proteins and microbiota also...
Source: Biochemical Society Transactions - January 15, 2021 Category: Biochemistry Authors: Pacheco-Fernandez T, Volpedo G, Verma C, Satoskar AR Tags: Biochem Soc Trans Source Type: research

Aneuploidy in human eggs: contributions of the meiotic spindle.
Abstract Human eggs frequently contain an incorrect number of chromosomes, a condition termed aneuploidy. Aneuploidy affects ∼10-25% of eggs in women in their early 30s, and more than 50% of eggs from women over 40. Most aneuploid eggs cannot develop to term upon fertilization, making aneuploidy in eggs a leading cause of miscarriages and infertility. The cellular origins of aneuploidy in human eggs are incompletely understood. Aneuploidy arises from chromosome segregation errors during the two meiotic divisions of the oocyte, the progenitor cell of the egg. Chromosome segregation is driven by a microtubule sp...
Source: Biochemical Society Transactions - January 15, 2021 Category: Biochemistry Authors: Thomas C, Cavazza T, Schuh M Tags: Biochem Soc Trans Source Type: research

The effect of Irisin on bone cells in vivo and in vitro.
Abstract The myokine Irisin, produced during physical exercise, has an anabolic effect on bone, both in vitro and in vivo. Very recently, using a controlled in vitro 3D cell model to mimic the bone microenvironment aboard the International Space Station, it has been shown that Irisin treatment in microgravity prevents the down-regulation of the transcription factors Atf4, Runx2 and Osterix, as well as Collagen I and Osteoprotegerin proteins, crucial for osteoblast differentiation in physiologic conditions. Irisin action has also been investigated in human subjects, in which it correlates with bone health status, s...
Source: Biochemical Society Transactions - January 15, 2021 Category: Biochemistry Authors: Buccoliero C, Oranger A, Colaianni G, Pignataro P, Zerlotin R, Lovero R, Errede M, Grano M Tags: Biochem Soc Trans Source Type: research

Towards structure-focused glycoproteomics.
Abstract Facilitated by advances in the separation sciences, mass spectrometry and informatics, glycoproteomics, the analysis of intact glycopeptides at scale, has recently matured enabling new insights into the complex glycoproteome. While diverse quantitative glycoproteomics strategies capable of mapping monosaccharide compositions of N- and O-linked glycans to discrete sites of proteins within complex biological mixtures with considerable sensitivity, quantitative accuracy and coverage have become available, developments supporting the advancement of structure-focused glycoproteomics, a recognised frontier in t...
Source: Biochemical Society Transactions - January 13, 2021 Category: Biochemistry Authors: Chernykh A, Kawahara R, Thaysen-Andersen M Tags: Biochem Soc Trans Source Type: research

Combinatorial biosynthesis for the generation of new-to-nature peptide antimicrobials.
Abstract Natural peptide products are a valuable source of important therapeutic agents, including antibiotics, antivirals and crop protection agents. Aided by an increased understanding of structure-activity relationships of these complex molecules and the biosynthetic machineries that produce them, it has become possible to re-engineer complete machineries and biosynthetic pathways to create novel products with improved pharmacological properties or modified structures to combat antimicrobial resistance. In this review, we will address the progress that has been made using non-ribosomally produced peptides and r...
Source: Biochemical Society Transactions - January 13, 2021 Category: Biochemistry Authors: Ruijne F, Kuipers OP Tags: Biochem Soc Trans Source Type: research

Antivirals that target the host IMP α/β1-virus interface.
Antivirals that target the host IMPα/β1-virus interface. Biochem Soc Trans. 2021 Jan 13;: Authors: Martin AJ, Jans DA Abstract Although transport into the nucleus mediated by the importin (IMP) α/β1-heterodimer is central to viral infection, small molecule inhibitors of IMPα/β1-dependent nuclear import have only been described and shown to have antiviral activity in the last decade. Their robust antiviral activity is due to the strong reliance of many different viruses, including RNA viruses such as human immunodeficiency virus-1 (HIV-1), dengue (DENV), and Zika (ZIKV)...
Source: Biochemical Society Transactions - January 13, 2021 Category: Biochemistry Authors: Martin AJ, Jans DA Tags: Biochem Soc Trans Source Type: research

Emerging role of VCP/p97 in cardiovascular diseases: novel insights and therapeutic opportunities.
Abstract Valosin-containing protein (VCP/p97) is a member of the conserved type II AAA+ (ATPases associated with diverse cellular activities) family of proteins with multiple biological functions, especially in protein homeostasis. Mutations in VCP/p97 are reportedly related to unique autosomal dominant diseases, which may worsen cardiac function. Although the structure of VCP/p97 has been clearly characterized, with reports of high abundance in the heart, research focusing on the molecular mechanisms underpinning the roles of VCP/p97 in the cardiovascular system has been recently undertaken over the past decades....
Source: Biochemical Society Transactions - January 13, 2021 Category: Biochemistry Authors: Shu H, Peng Y, Hang W, Zhou N, Wang DW Tags: Biochem Soc Trans Source Type: research

Glycosome heterogeneity in kinetoplastids.
Abstract Kinetoplastid parasites have essential organelles called glycosomes that are analogous to peroxisomes present in other eukaryotes. While many of the processes that regulate glycosomes are conserved, there are several unique aspects of their biology that are divergent from other systems and may be leveraged as therapeutic targets for the treatment of kinetoplastid diseases. Glycosomes are heterogeneous organelles that likely exist as sub-populations with different protein composition and function in a given cell, between individual cells, and between species. However, the limitations posed by the small siz...
Source: Biochemical Society Transactions - January 13, 2021 Category: Biochemistry Authors: Crowe LP, Morris MT Tags: Biochem Soc Trans Source Type: research

RNA transfer through tunneling nanotubes.
Abstract It was already suggested in the early '70's that RNA molecules might transfer between mammalian cells in culture. Yet, more direct evidence for RNA transfer in animal and plant cells was only provided decades later, as this field became established. In this mini-review, we will describe evidence for the transfer of different types of RNA between cells through tunneling nanotubes (TNTs). TNTs are long, yet thin, open-ended cellular protrusions that are structurally distinct from filopodia. TNTs connect cells and can transfer many types of cargo, including small molecules, proteins, vesicles, pathogens, and...
Source: Biochemical Society Transactions - December 24, 2020 Category: Biochemistry Authors: Haimovich G, Dasgupta S, Gerst JE Tags: Biochem Soc Trans Source Type: research

Inhibition of RAF dimers: it takes two to tango.
Abstract The RAS-regulated RAF-MEK1/2-ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix...
Source: Biochemical Society Transactions - December 24, 2020 Category: Biochemistry Authors: Cook FA, Cook SJ Tags: Biochem Soc Trans Source Type: research

Solid-state NMR approaches to investigate large enzymes in complex with substrates and inhibitors.
AK Abstract Enzyme catalysis is omnipresent in the cell. The mechanisms by which highly evolved protein folds enable rapid and specific chemical transformation of substrates belong to the marvels of structural biology. Targeting of enzymes with inhibitors has immediate application in drug discovery, from chemotherapeutics over antibiotics to antivirals. NMR spectroscopy combines multiple assets for the investigation of enzyme function. The non-invasive technique can probe enzyme structure and dynamics and map interactions with substrates, cofactors and inhibitors at the atomic level. With experiments performed at...
Source: Biochemical Society Transactions - December 24, 2020 Category: Biochemistry Authors: Schütz AK Tags: Biochem Soc Trans Source Type: research

Structure and regulation of coronavirus genomes: state-of-the-art and novel insights from SARS-CoV-2 studies.
Abstract Coronaviruses (CoV) are positive-sense single-stranded RNA viruses, harboring the largest viral RNA genomes known to date. Apart from the primary sequence encoding for all the viral proteins needed for the generation of new viral particles, certain regions of CoV genomes are known to fold into stable structures, controlling several aspects of CoV life cycle, from the regulation of the discontinuous transcription of subgenomic mRNAs, to the packaging of the genome into new virions. Here we review the current knowledge on CoV RNA structures, discussing it in light of the most recent discoveries made possibl...
Source: Biochemical Society Transactions - December 24, 2020 Category: Biochemistry Authors: Manfredonia I, Incarnato D Tags: Biochem Soc Trans Source Type: research

Multifunctionality of F-rich nucleoporins.
e EA Abstract Nucleoporins (Nups) represent a range of proteins most known for composing the macromolecular assembly of the nuclear pore complex (NPC). Among them, the family of intrinsically disordered proteins (IDPs) phenylalanine-glycine (FG) rich Nups, form the permeability barrier and coordinate the high-speed nucleocytoplasmic transport in a selective way. Those FG-Nups have been demonstrated to participate in various biological processes besides nucleocytoplasmic transport. The high number of accessible hydrophobic motifs of FG-Nups potentially gives rise to this multifunctionality, enabling them to form un...
Source: Biochemical Society Transactions - December 18, 2020 Category: Biochemistry Authors: Heinß N, Sushkin M, Yu M, Lemke EA Tags: Biochem Soc Trans Source Type: research

Developments in tandem ion mobility mass spectrometry.
Abstract Ion Mobility (IM) coupled to mass spectrometry (MS) is a useful tool for separating species of interest out of small quantities of heterogenous mixtures via a combination of m/z and molecular shape. While tandem MS instruments are common, instruments which employ tandem IM are less so with the first commercial IM-MS instrument capable of multiple IM selection rounds being released in 2019. Here we explore the history of tandem IM instruments, recent developments, the applications to biological systems and expected future directions. PMID: 33336686 [PubMed - as supplied by publisher] (Source: Biochemi...
Source: Biochemical Society Transactions - December 18, 2020 Category: Biochemistry Authors: Eldrid C, Thalassinos K Tags: Biochem Soc Trans Source Type: research

Keeping your options open: insights from Dppa2/4 into how epigenetic priming factors promote cell plasticity.
Abstract The concept of cellular plasticity is particularly apt in early embryonic development, where there is a tug-of-war between the stability and flexibility of cell identity. This balance is controlled in part through epigenetic mechanisms. Epigenetic plasticity dictates how malleable cells are to change by adjusting the potential to initiate new transcriptional programmes. The higher the plasticity of a cell, the more readily it can adapt and change its identity in response to external stimuli such as differentiation cues. Epigenetic plasticity is regulated in part through the action of epigenetic priming fa...
Source: Biochemical Society Transactions - December 18, 2020 Category: Biochemistry Authors: Eckersley-Maslin MA Tags: Biochem Soc Trans Source Type: research

Plant cell divisions: variations from the shortest symmetric path.
Abstract In plants, the spatial arrangement of cells within tissues and organs is a direct consequence of the positioning of the new cell walls during cell division. Since the nineteenth century, scientists have proposed rules to explain the orientation of plant cell divisions. Most of these rules predict the new wall will follow the shortest path passing through the cell centroid halving the cell into two equal volumes. However, in some developmental contexts, divisions deviate significantly from this rule. In these situations, mechanical stress, hormonal signalling, or cell polarity have been described to influe...
Source: Biochemical Society Transactions - December 18, 2020 Category: Biochemistry Authors: Serra L, Robinson S Tags: Biochem Soc Trans Source Type: research

Correction: Emerging aspects in the regulation of ferroptosis.
PMID: 33336694 [PubMed - as supplied by publisher] (Source: Biochemical Society Transactions)
Source: Biochemical Society Transactions - December 18, 2020 Category: Biochemistry Authors: Nehring H, Meierjohann S, Angeli JPF Tags: Biochem Soc Trans Source Type: research

Protein-membrane interactions in small GTPase signalling and pharmacology: perspectives from Arf GTPases studies.
Abstract Small GTPases, in association with their GEFs, GAPs and effectors, control major intracellular processes such as signal transduction, cytoskeletal dynamics and membrane trafficking. Accordingly, dysfunctions in their biochemical properties are associated with many diseases, including cancers, diabetes, infections, mental disorders and cardiac diseases, which makes them attractive targets for therapies. However, small GTPases signalling modules are not well-suited for classical inhibition strategies due to their mode of action that combines protein-protein and protein-membrane interactions. As a consequenc...
Source: Biochemical Society Transactions - December 18, 2020 Category: Biochemistry Authors: Nawrotek A, Zeghouf M, Cherfils J Tags: Biochem Soc Trans Source Type: research

Connecting the dots: combined control of endocytic recycling and degradation.
Abstract Endocytosis is an essential process where proteins and lipids are internalised from the plasma membrane in membrane-bound carriers, such as clathrin-coated vesicles. Once internalised into the cell these vesicles fuse with the endocytic network where their contents are sorted towards degradation in the lysosome or recycling to their origin. Initially, it was thought that cargo recycling is a passive process, but in recent years the identification and characterisation of specialised recycling complexes has established a hitherto unthought-of level of complexity that actively opposes degradation. This revie...
Source: Biochemical Society Transactions - December 10, 2020 Category: Biochemistry Authors: MacDonald E, Savage B, Zech T Tags: Biochem Soc Trans Source Type: research

Biofilm and swarming emergent behaviours controlled through the aid of biophysical understanding and tools.
Abstract Bacteria can organise themselves into communities in the forms of biofilms and swarms. Through chemical and physical interactions between cells, these communities exhibit emergent properties that individual cells alone do not have. While bacterial communities have been mainly studied in the context of biochemistry and molecular biology, recent years have seen rapid advancements in the biophysical understanding of emergent phenomena through physical interactions in biofilms and swarms. Moreover, new technologies to control bacterial emergent behaviours by physical means are emerging in synthetic biology. S...
Source: Biochemical Society Transactions - December 10, 2020 Category: Biochemistry Authors: Grobas I, Bazzoli DG, Asally M Tags: Biochem Soc Trans Source Type: research

Anatomy of a twin DNA replication factory.
Abstract The replication of DNA in chromosomes is initiated at sequences called origins at which two replisome machines are assembled at replication forks that move in opposite directions. Interestingly, in vivo studies observe that the two replication forks remain fastened together, often referred to as a replication factory. Replication factories containing two replisomes are well documented in cellular studies of bacteria (Escherichia coli and Bacillus subtilis) and the eukaryote, Saccharomyces cerevisiae. This basic twin replisome factory architecture may also be preserved in higher eukaryotes. Despite many ye...
Source: Biochemical Society Transactions - December 10, 2020 Category: Biochemistry Authors: Li H, Yao NY, O'Donnell ME Tags: Biochem Soc Trans Source Type: research

The impact of photorespiration on plant primary metabolism through metabolic and redox regulation.
Abstract Photorespiration is an inevitable trait of all oxygenic phototrophs, being the only known metabolic route that converts the inhibitory side-product of Rubisco's oxygenase activity 2-phosphoglycolate (2PG) back into the Calvin-Benson (CB) cycle's intermediate 3-phosphoglycerate (3PGA). Through this function of metabolite repair, photorespiration is able to protect photosynthetic carbon assimilation from the metabolite intoxication that would occur in the present-day oxygen-rich atmosphere. In recent years, much plant research has provided compelling evidence that photorespiration safeguards photosynthesis ...
Source: Biochemical Society Transactions - December 10, 2020 Category: Biochemistry Authors: Timm S Tags: Biochem Soc Trans Source Type: research

Dissecting the complexity of biomolecular condensates.
Abstract Biomolecular condensates comprise a diverse and ubiquitous class of membraneless organelles. Condensate assembly is often described by liquid-liquid phase separation. While this process explains many key features, it cannot account for the compositional or architectural complexity that condensates display in cells. Recent work has begun to dissect the rich network of intermolecular interactions that give rise to biomolecular condensates. Here, we review the latest results from theory, simulations and experiments, and discuss what they reveal about the structure-function relationship of condensates. P...
Source: Biochemical Society Transactions - December 10, 2020 Category: Biochemistry Authors: Swain P, Weber SC Tags: Biochem Soc Trans Source Type: research

Nuclear import of histones.
Abstract The transport of histones from the cytoplasm to the nucleus of the cell, through the nuclear membrane, is a cellular process that regulates the supply of new histones in the nucleus and is key for DNA replication and transcription. Nuclear import of histones is mediated by proteins of the karyopherin family of nuclear transport receptors. Karyopherins recognize their cargos through linear motifs known as nuclear localization/export sequences or through folded domains in the cargos. Karyopherins interact with nucleoporins, proteins that form the nuclear pore complex, to promote the translocation of their c...
Source: Biochemical Society Transactions - December 10, 2020 Category: Biochemistry Authors: Bernardes NE, Chook YM Tags: Biochem Soc Trans Source Type: research

Turning the Mre11/Rad50 DNA repair complex on its head: lessons from SMC protein hinges, dynamic coiled-coil movements and DNA loop-extrusion?
Abstract The bacterial SbcC/SbcD DNA repair proteins were identified over a quarter of a century ago. Following the subsequent identification of the homologous Mre11/Rad50 complex in the eukaryotes and archaea, it has become clear that this conserved chromosomal processing machinery is central to DNA repair pathways and the maintenance of genomic stability in all forms of life. A number of experimental studies have explored this intriguing genome surveillance machinery, yielding significant insights and providing conceptual advances towards our understanding of how this complex operates to mediate DNA repair. Howe...
Source: Biochemical Society Transactions - December 10, 2020 Category: Biochemistry Authors: Zabolotnaya E, Mela I, Henderson RM, Robinson NP Tags: Biochem Soc Trans Source Type: research

The emerging roles of semaphorin4D/CD100 in immunological diseases.
Abstract In vertebrates, the semaphorin family of proteins is composed of 21 members that are divided into five subfamilies, i.e. classes 3 to 7. Semaphorins play crucial roles in regulating multiple biological processes, such as neural remodeling, tissue regeneration, cancer progression, and, especially, in immunological regulation. Semaphorin 4D (SEMA4D), also known as CD100, is an important member of the semaphorin family and was first characterized as a lymphocyte-specific marker. SEMA4D has diverse effects on immunologic processes, including immune cell proliferation, differentiation, activation, and migratio...
Source: Biochemical Society Transactions - December 1, 2020 Category: Biochemistry Authors: Wang L, Li X, Song Y, Song D, Huang D Tags: Biochem Soc Trans Source Type: research

Multifaceted roles of long non-coding RNAs in triple-negative breast cancer: biology and clinical applications.
Abstract Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype that lacks targeted therapy due to the absence of estrogen, progesterone, and HER2 receptors. Moreover, TNBC was shown to have a poor prognosis, since it involves aggressive phenotypes that confer significant hindrance to therapeutic treatments. Recent state-of-the-art sequencing technologies have shed light on several long non-coding RNAs (lncRNAs), previously thought to have no biological function and were considered as genomic junk. LncRNAs are involved in various physiological as well as pathological conditions, and play a k...
Source: Biochemical Society Transactions - December 1, 2020 Category: Biochemistry Authors: Rajagopal T, Talluri S, Venkatabalasubramanian S, Dunna NR Tags: Biochem Soc Trans Source Type: research

A pocket guide on how to structure SARS-CoV-2 drugs and therapies.
Abstract The race to identify a successful treatment for COVID19 will be defined by fundamental research into the replication cycle of the SARS-CoV-2 virus. This has identified five distinct stages from which numerous vaccination and clinical trials have emerged alongside an innumerable number of drug discovery studies currently in development for disease intervention. Informing every step of the viral replication cycle has been an unprecedented 'call-to-arms' by the global structural biology community. Of the 20 main SARS-CoV-2 proteins, 13 have been resolved structurally for SARS-CoV-2 with most having a related...
Source: Biochemical Society Transactions - December 1, 2020 Category: Biochemistry Authors: Littler DR, MacLachlan BJ, Watson GM, Vivian JP, Gully BS Tags: Biochem Soc Trans Source Type: research

New perspectives of the cardiac cellular landscape: mapping cellular mediators of cardiac fibrosis using single-cell transcriptomics.
Abstract Single-cell transcriptomics enables inference of context-dependent phenotypes of individual cells and determination of cellular diversity of complex tissues. Cardiac fibrosis is a leading factor in the development of heart failure and a major cause of morbidity and mortality worldwide with no effective treatment. Single-cell RNA-sequencing (scRNA-seq) offers a promising new platform to identify new cellular and molecular protagonists that may drive cardiac fibrosis and development of heart failure. This review will summarize the application scRNA-seq for understanding cardiac fibrosis and development of h...
Source: Biochemical Society Transactions - December 1, 2020 Category: Biochemistry Authors: Krstevski C, Cohen CD, Dona MSI, Pinto AR Tags: Biochem Soc Trans Source Type: research

Varicella-zoster virus: molecular controls of cell fusion-dependent pathogenesis.
Abstract Varicella-zoster virus (VZV) is the causative agent of chicken pox (varicella) and shingles (zoster). Although considered benign diseases, both varicella and zoster can cause complications. Zoster is painful and can lead to post herpetic neuralgia. VZV has also been linked to stroke, related to giant cell arteritis in some cases. Vaccines are available but the attenuated vaccine is not recommended in immunocompromised individuals and the efficacy of the glycoprotein E (gE) based subunit vaccine has not been evaluated for the prevention of varicella. A hallmark of VZV pathology is the formation of multinuc...
Source: Biochemical Society Transactions - December 1, 2020 Category: Biochemistry Authors: Oliver SL, Zhou M, Arvin AM Tags: Biochem Soc Trans Source Type: research

RNA matchmaking in chromatin regulation.
Abstract Beyond being the product of gene expression, RNA can also influence the regulation of chromatin. The majority of the human genome has the capacity to be transcribed and the majority of the non-protein-coding transcripts made by RNA Polymerase II are enriched in the nucleus. Many chromatin regulators can bind to these ncRNAs in the nucleus; in some cases, there are clear examples of direct RNA-mediated chromatin regulation mechanisms stemming from these interactions, while others have yet to be determined. Recent studies have highlighted examples of chromatin regulation via RNA matchmaking, a term we use b...
Source: Biochemical Society Transactions - November 27, 2020 Category: Biochemistry Authors: Wu SK, Roberts JT, Balas MM, Johnson AM Tags: Biochem Soc Trans Source Type: research

Post-transcriptional control of mitochondrial protein composition in changing environmental conditions.
Abstract In fluctuating environmental conditions, organisms must modulate their bioenergetic production in order to maintain cellular homeostasis for optimal fitness. Mitochondria are hubs for metabolite and energy generation. Mitochondria are also highly dynamic in their function: modulating their composition, size, density, and the network-like architecture in relation to the metabolic demands of the cell. Here, we review the recent research on the post-transcriptional regulation of mitochondrial composition focusing on mRNA localization, mRNA translation, protein import, and the role that dynamic mitochondrial ...
Source: Biochemical Society Transactions - November 27, 2020 Category: Biochemistry Authors: Tsuboi T, Leff J, Zid BM Tags: Biochem Soc Trans Source Type: research

Beyond the pan-genome: current perspectives on the functional and practical outcomes of the distributed genome hypothesis.
Abstract The principle of monoclonality with regard to bacterial infections was considered immutable prior to 30 years ago. This view, espoused by Koch for acute infections, has proven inadequate regarding chronic infections as persistence requires multiple forms of heterogeneity among the bacterial population. This understanding of bacterial plurality emerged from a synthesis of what-were-then novel technologies in molecular biology and imaging science. These technologies demonstrated that bacteria have complex life cycles, polymicrobial ecologies, and evolve in situ via the horizontal exchange of genic character...
Source: Biochemical Society Transactions - November 27, 2020 Category: Biochemistry Authors: Hammond JA, Gordon EA, Socarras KM, Chang Mell J, Ehrlich GD Tags: Biochem Soc Trans Source Type: research

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