Position effects on promoter activity in Escherichia coli and their consequences for antibiotic-resistance determinants.
Abstract The activity of any bacterial promoter is generally supposed to be set by its base sequence and the different transcription factors that bind in the local vicinity. Here, we review recent data indicating that the activity of the Escherichia coli lac operon promoter also depends upon its chromosomal location. Factors that affect promoter activity include the binding of nucleoid-associated proteins to neighbouring sequences, supercoiling and the activity of neighbouring promoters. We suggest that many bacterial promoters might be susceptible to similar position-dependent effects and we review recent data sh...
Source: Biochemical Society Transactions - June 12, 2019 Category: Biochemistry Authors: Cooke K, Browning DF, Lee DJ, Blair JMA, McNeill HE, Huber D, Busby SJW, Bryant JA Tags: Biochem Soc Trans Source Type: research

Polyploidy in halophilic archaea: regulation, evolutionary advantages, and gene conversion.
Abstract All analyzed haloarachea are polyploid. In addition, haloarchaea contain more than one type of chromosome, and thus the gene dosage can be regulated independently on different replicons. Haloarchaea and several additional archaea have more than one replication origin on their major chromosome, in stark contrast with bacteria, which have a single replication origin. Two of these replication origins of Haloferax volcanii have been studied in detail and turned out to have very different properties. The chromosome copy number appears to be regulated in response to growth phases and environmental factors. Arch...
Source: Biochemical Society Transactions - June 12, 2019 Category: Biochemistry Authors: Ludt K, Soppa J Tags: Biochem Soc Trans Source Type: research

Catalytic mechanism of UDP-glucose dehydrogenase.
Abstract UDP-glucose dehydrogenase (UGDH), an oxidoreductase, catalyzes the NAD+-dependent four-electron oxidation of UDP-glucose to UDP-glucuronic acid. The catalytic mechanism of UGDH remains controversial despite extensive investigation and is classified into two types according to whether an aldehyde intermediate is generated in the first oxidation step. The first type, which involves the presence of this putative aldehyde, is inconsistent with some experimental findings. In contrast, the second type, which indicates that the first oxidation step bypasses the aldehyde via an NAD+-dependent bimolecular nucleoph...
Source: Biochemical Society Transactions - June 12, 2019 Category: Biochemistry Authors: Chen J, Yang S Tags: Biochem Soc Trans Source Type: research

Correction: Nucleotide modifications in messenger RNA and their role in development and disease.
PMID: 31189735 [PubMed - as supplied by publisher] (Source: Biochemical Society Transactions)
Source: Biochemical Society Transactions - June 12, 2019 Category: Biochemistry Authors: Dezi V, Ivanov C, Haussmann IU, Soller M Tags: Biochem Soc Trans Source Type: research

Lipid-dependent Akt-ivity: where, when, and how.
Abstract Akt is an essential protein kinase activated downstream of phosphoinositide 3-kinase and frequently hyperactivated in cancer. Canonically, Akt is activated by phosphoinositide-dependent kinase 1 and mechanistic target of rapamycin complex 2, which phosphorylate it on two regulatory residues in its kinase domain upon targeting of Akt to the plasma membrane by PI(3,4,5)P3 Recent evidence, however, has shown that, in addition to phosphorylation, Akt activity is allosterically coupled to the engagement of PI(3,4,5)P3 or PI(3,4)P2 in cellular membranes. Furthermore, the active membrane-bound conformation of Ak...
Source: Biochemical Society Transactions - May 30, 2019 Category: Biochemistry Authors: Siess KM, Leonard TA Tags: Biochem Soc Trans Source Type: research

Advances in the molecular regulation of endothelial BMP9 signalling complexes and implications for cardiovascular disease.
Abstract Bone morphogenetic protein 9 (BMP9), a member of the transforming growth factor β (TGFβ) superfamily, is a circulating vascular quiescence and endothelial protective factor, accounting for the majority of BMP activities in plasma. BMP9 and BMP10 bind preferentially to the high-affinity type I receptor activin receptor-like kinase 1 on vascular endothelial cells. Recently, many reports have highlighted the important roles of BMP9 in cardiovascular disease, particularly pulmonary arterial hypertension. In vivo, BMP9 activity and specificity are determined by tightly regulated protein-protein recog...
Source: Biochemical Society Transactions - May 24, 2019 Category: Biochemistry Authors: Wood JH, Guo J, Morrell NW, Li W Tags: Biochem Soc Trans Source Type: research

Biology is the root of variability: cautionary tales in Caenorhabditis elegans biology.
Abstract Reproducibility is critical for the standardization, interpretation, and progression of research. However, many factors increase variability and reduce reproducibility. In Caenorhabditis elegans research, there are many possible causes of variability that may explain why experimental outcomes sometimes differ between laboratories and between experiments. Factors contributing to experimental variability include the genetic background of both C. elegans and its bacterial diet, differences in media composition, intergenerational and transgenerational effects that may be carried over for generations, and the ...
Source: Biochemical Society Transactions - May 24, 2019 Category: Biochemistry Authors: Pho KB, MacNeil LT Tags: Biochem Soc Trans Source Type: research

Bacteriophage gene products as potential antimicrobials against tuberculosis.
Abstract Tuberculosis (TB) is recognised as one of the most pressing global health threats among infectious diseases. Bacteriophages are adapted for killing of their host, and they were exploited in antibacterial therapy already before the discovery of antibiotics. Antibiotics as broadly active drugs overshadowed phage therapy for a long time. However, owing to the rapid spread of antibiotic resistance and the increasing complexity of treatment of drug-resistant TB, mycobacteriophages are being studied for their antimicrobial potential. Besides phage therapy, which is the administration of live phages to infected ...
Source: Biochemical Society Transactions - May 13, 2019 Category: Biochemistry Authors: Puiu M, Julius C Tags: Biochem Soc Trans Source Type: research

Investigating targets for neuropharmacological intervention by molecular dynamics simulations.
Abstract Medical research has identified over 500 brain disorders. Among these, there are still only very few neuropathologies whose causes are fully understood and, consequently, very few drugs whose mechanism of action is known. No FDA drug has been identified for major neurodegenerative diseases, such as Alzheimer's and Parkinson's. We still lack effective treatments and strategies for modulating progression or even early neurodegenerative disease onset diagnostic tools. A great support toward the highly needed identification of neuroactive drugs comes from computer simulation methods and, in particular, from m...
Source: Biochemical Society Transactions - May 13, 2019 Category: Biochemistry Authors: Rossetti G, Kless A, Lai L, Outeiro TF, Carloni P Tags: Biochem Soc Trans Source Type: research

Liposomes as models for membrane integrity.
Abstract Biological membranes form the boundaries to cells. They are integral to cellular function, retaining the valuable components inside and preventing access of unwanted molecules. Many different classes of molecules demonstrate disruptive properties to the plasma membrane. These include alcohols, detergents and antimicrobial agents. Understanding this disruption and the mechanisms by which it can be mitigated is vital for improved therapeutics as well as enhanced industrial processes where the compounds produced can be toxic to the membrane. This mini-review describes the most common molecules that disrupt c...
Source: Biochemical Society Transactions - May 13, 2019 Category: Biochemistry Authors: Routledge SJ, Linney JA, Goddard AD Tags: Biochem Soc Trans Source Type: research

LRRK2, alpha-synuclein, and tau: partners in crime or unfortunate bystanders?
Abstract The identification of genetic forms of Parkinson's disease (PD) has tremendously expanded our understanding of the players and mechanisms involved. Mutations in the genes encoding for alpha-synuclein (aSyn), LRRK2, and tau have been associated with familial and sporadic forms of the disease. aSyn is the major component of Lewy bodies and Lewy neurites, which are pathognomonic protein inclusions in PD. Hyperphosphorylated tau protein accumulates in neurofibrillary tangles in the brains of Alzheimer's disease patients but is also seen in the brains of PD patients. LRRK2 is a complex multi-domain protein wit...
Source: Biochemical Society Transactions - May 13, 2019 Category: Biochemistry Authors: Outeiro TF, Harvey K, Dominguez-Meijide A, Gerhardt E Tags: Biochem Soc Trans Source Type: research

Engineering quorum quenching enzymes: progress and perspectives.
Abstract Quorum sensing is a key contributor to the virulence of many important plant, animal and human pathogens. The disruption of this signalling-a process referred to as 'quorum quenching'-is a promising new approach for controlling microbial pathogens. In this mini-review, we have focused on efforts to engineer enzymes that disrupt quorum sensing by inactivating acyl-homoserine lactone signalling molecules. We review different approaches for protein engineering and provide examples of how these engineering approaches have been used to tailor the stability, specificity and activities of quorum quenching enzyme...
Source: Biochemical Society Transactions - May 7, 2019 Category: Biochemistry Authors: Murugayah SA, Gerth ML Tags: Biochem Soc Trans Source Type: research

MT1-MMP-dependent cell migration: proteolytic and non-proteolytic mechanisms.
Abstract Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a type I transmembrane proteinase that belongs to the matrix metalloproteinase (MMP) family. It is a potent modifier of cellular microenvironment and promotes cell migration and invasion of a wide variety of cell types both in physiological and pathological conditions. It promotes cell migration by degrading extracellular matrix on the cell surface and creates a migration path, by modifying cell adhesion property by shedding cell adhesion molecules to increase cell motility, and by altering cellular metabolism. Thus, MT1-MMP is a multifunctional cell m...
Source: Biochemical Society Transactions - May 7, 2019 Category: Biochemistry Authors: Gifford V, Itoh Y Tags: Biochem Soc Trans Source Type: research

How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers.
Abstract Point mutations in the coding sequence for solute carrier 6 (SLC6) family members result in clinically relevant disorders, which are often accounted for by a loss-of-function phenotype. In many instances, the mutated transporter is not delivered to the cell surface because it is retained in the endoplasmic reticulum (ER). The underlying defect is improper folding of the transporter and is the case for many of the known dopamine transporter mutants. The monoamine transporters, i.e. the transporters for norepinephrine (NET/SLC6A2), dopamine (DAT/SLC6A3) and serotonin (SERT/SLC6A4), have a rich pharmacology;...
Source: Biochemical Society Transactions - May 7, 2019 Category: Biochemistry Authors: Bhat S, Newman AH, Freissmuth M Tags: Biochem Soc Trans Source Type: research

Allosteric regulation of AMP-activated protein kinase by adenylate nucleotides and small-molecule drugs.
Abstract The AMP (adenosine 5'-monophosphate)-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis that co-ordinates metabolic processes to ensure energy supply meets demand. At the cellular level, AMPK is activated by metabolic stresses that increase AMP or adenosine 5'-diphosphate (ADP) coupled with falling adenosine 5'-triphosphate (ATP) and acts to restore energy balance by choreographing a shift in metabolism in favour of energy-producing catabolic pathways while inhibiting non-essential anabolic processes. AMPK also regulates systemic energy balance and is activate...
Source: Biochemical Society Transactions - April 18, 2019 Category: Biochemistry Authors: de Souza Almeida Matos AL, Oakhill JS, Moreira J, Loh K, Galic S, Scott JW Tags: Biochem Soc Trans Source Type: research

Exploitation of the Escherichia coli lac operon promoter for controlled recombinant protein production.
Abstract The Escherichia coli lac operon promoter is widely used as a tool to control recombinant protein production in bacteria. Here, we give a brief review of how it functions, how it is regulated, and how, based on this knowledge, a suite of lac promoter derivatives has been developed to give a controlled expression that is suitable for diverse biotechnology applications. PMID: 30971435 [PubMed - as supplied by publisher] (Source: Biochemical Society Transactions)
Source: Biochemical Society Transactions - April 10, 2019 Category: Biochemistry Authors: Browning DF, Godfrey RE, Richards KL, Robinson C, Busby SJW Tags: Biochem Soc Trans Source Type: research

Imaging cell morphology and physiology using X-rays.
Abstract Morphometric measurements, such as quantifying cell shape, characterizing sub-cellular organization, and probing cell-cell interactions, are fundamental in cell biology and clinical medicine. Until quite recently, the main source of morphometric data on cells has been light- and electron-based microscope images. However, many technological advances have propelled X-ray microscopy into becoming another source of high-quality morphometric information. Here, we review the status of X-ray microscopy as a quantitative biological imaging modality. We also describe the combination of X-ray microscopy data with i...
Source: Biochemical Society Transactions - April 5, 2019 Category: Biochemistry Authors: Weinhardt V, Chen JH, Ekman A, McDermott G, Le Gros MA, Larabell C Tags: Biochem Soc Trans Source Type: research

Apoptotic cell-derived extracellular vesicles: structure-function relationships.
Abstract Apoptosis is an essential process for normal physiology and plays a key role in the resolution of inflammation. Clearance of apoptotic cells (ACs) involves complex signalling between phagocytic cells, ACs, and the extracellular vesicles (EVs) they produce. Here, we discuss apoptotic cell-derived extracellular vesicles (ACdEVs) and how their structure relates to their function in AC clearance and the control of inflammation, focussing on the ACdEV proteome. We review the current knowledge, ongoing work and future directions for research in this field. PMID: 30952802 [PubMed - as supplied by publisher]...
Source: Biochemical Society Transactions - April 5, 2019 Category: Biochemistry Authors: Grant LR, Milic I, Devitt A Tags: Biochem Soc Trans Source Type: research

Packaging development: how chromatin controls transcription in zebrafish embryogenesis.
Abstract How developmental gene expression is activated, co-ordinated and maintained is one of the biggest questions in developmental biology. While transcription factors lead the way in directing developmental gene expression, their accessibility to the correct repertoire of genes can depend on other factors such as DNA methylation, the presence of particular histone variants and post-translational modifications of histones. Collectively, factors that modify DNA or affect its packaging and accessibility contribute to a chromatin landscape that helps to control the timely expression of developmental genes. Zebrafi...
Source: Biochemical Society Transactions - April 5, 2019 Category: Biochemistry Authors: Horsfield JA Tags: Biochem Soc Trans Source Type: research

Oxysterol research: a brief review.
Abstract In the present study, we discuss the recent developments in oxysterol research. Exciting results have been reported relating to the involvement of oxysterols in the fields of neurodegenerative disease, especially in Huntington's disease, Parkinson's disease and Alzheimer's disease; in signalling and development, in particular, in relation to Hedgehog signalling; and in cancer, with a special focus on (25R)26-hydroxycholesterol. Methods for the measurement of oxysterols, essential for understanding their mechanism of action in vivo, and valuable for diagnosing rare diseases of cholesterol biosynthesis and ...
Source: Biochemical Society Transactions - April 1, 2019 Category: Biochemistry Authors: Griffiths WJ, Wang Y Tags: Biochem Soc Trans Source Type: research

Amino acid transporters in the regulation of insulin secretion and signalling.
Abstract Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid t...
Source: Biochemical Society Transactions - April 1, 2019 Category: Biochemistry Authors: Javed K, Fairweather SJ Tags: Biochem Soc Trans Source Type: research

Manipulating nitrogen regulation in diazotrophic bacteria for agronomic benefit.
Abstract Biological nitrogen fixation (BNF) is controlled by intricate regulatory mechanisms to ensure that fixed nitrogen is readily assimilated into biomass and not released to the environment. Understanding the complex regulatory circuits that couple nitrogen fixation to ammonium assimilation is a prerequisite for engineering diazotrophic strains that can potentially supply fixed nitrogen to non-legume crops. In this review, we explore how the current knowledge of nitrogen metabolism and BNF regulation may allow strategies for genetic manipulation of diazotrophs for ammonia excretion and provide a contribution ...
Source: Biochemical Society Transactions - April 1, 2019 Category: Biochemistry Authors: Bueno Batista M, Dixon R Tags: Biochem Soc Trans Source Type: research

The role of the 12(S)-HETE/GPR31/12-HETER axis in cancer and ischemia-reperfusion injury.
Abstract The G protein-coupled receptors (GPCRs) constitute a large superfamily of seven transmembrane-spanning receptors that are activated by several classes of ligands, including bioactive lipids. GPCRs are attractive therapeutic targets for the treatment of human diseases, as they finely regulate a wide array of cellular functions. In this minireview, we summarized what is currently known about the G protein-coupled receptor GPR31/12-HETER. We highlighted, in particular, its structural similarity with human homologs, the biological functions of its recognized ligand 12(S)-hydroxyeicosatetraenoic acid (HETE), a...
Source: Biochemical Society Transactions - March 22, 2019 Category: Biochemistry Authors: Napolitano M Tags: Biochem Soc Trans Source Type: research

Endothelial-to-haematopoietic transition: an update on the process of making blood.
Abstract The first definitive blood cells during embryogenesis are derived from endothelial cells in a highly conserved process known as endothelial-to-haematopoietic transition (EHT). This conversion involves activation of a haematopoietic transcriptional programme in a subset of endothelial cells in the major vasculature of the embryo, followed by major morphological changes that result in transitioning cells rounding up, breaking the tight junctions to neighbouring endothelial cells and adopting a haematopoietic fate. The whole process is co-ordinated by a complex interplay of key transcription factors and sign...
Source: Biochemical Society Transactions - March 22, 2019 Category: Biochemistry Authors: Ottersbach K Tags: Biochem Soc Trans Source Type: research

Recruited lysosomal enzymes as major digestive enzymes in insects.
Abstract The mass recruitment to the midgut contents of lysosomal proteolytic enzymes occurred in insects under three major selective pressures. Hemipteran (true bugs, aphids, and cicadas) ancestors lost their serine peptidases (SP) on adapting to feed on protein-free plant sap. When they returned to protein diets, their cathepsins L and B were recruited to replace their lost SP. Among beetles of the series Cucujiformia, cathepsins L were recruited to hydrolyze ingested plant inhibitors that affect their major SP and/or to deal with special seed proteins, such as prolamins. Larval flies have a very acid middle mid...
Source: Biochemical Society Transactions - March 22, 2019 Category: Biochemistry Authors: Terra WR, Dias RO, Ferreira C Tags: Biochem Soc Trans Source Type: research

Glioblastoma heterogeneity and the tumour microenvironment: implications for preclinical research and development of new treatments.
Abstract Glioblastoma is the deadliest form of brain cancer. Aside from inadequate treatment options, one of the main reasons glioblastoma is so lethal is the rapid growth of tumour cells coupled with continuous cell invasion into surrounding healthy brain tissue. Significant intra- and inter-tumour heterogeneity associated with differences in the corresponding tumour microenvironments contributes greatly to glioblastoma progression. Within this tumour microenvironment, the extracellular matrix profoundly influences the way cancer cells become invasive, and changes to extracellular (pH and oxygen levels) and metab...
Source: Biochemical Society Transactions - March 22, 2019 Category: Biochemistry Authors: Perrin SL, Samuel MS, Koszyca B, Brown MP, Ebert LM, Oksdath M, Gomez GA Tags: Biochem Soc Trans Source Type: research

United colours of chromatin? Developmental genome organisation in flies.
Abstract The organisation of DNA into differing forms of packaging, or chromatin, controls many of the cell fate decisions during development. Although early studies focused on individual forms of chromatin, in the last decade more holistic studies have attempted to determine a complete picture of the different forms of chromatin present within a cell. In the fruit fly, Drosophila melanogaster, the study of chromatin states has been aided by the use of complementary and cell-type-specific techniques that profile the marks that recruit chromatin protein binding or the proteins themselves. Although many questions re...
Source: Biochemical Society Transactions - March 22, 2019 Category: Biochemistry Authors: Delandre C, Marshall OJ Tags: Biochem Soc Trans Source Type: research

Protein engineering: the potential of remote mutations.
Abstract Engineered proteins, especially enzymes, are now commonly used in many industries owing to their catalytic power, specific binding of ligands, and properties as materials and food additives. As the number of potential uses for engineered proteins has increased, the interest in engineering or designing proteins to have greater stability, activity and specificity has increased in turn. With any rational engineering or design pursuit, the success of these endeavours relies on our fundamental understanding of the systems themselves; in the case of proteins, their structure-dynamics-function relationships. Pro...
Source: Biochemical Society Transactions - March 22, 2019 Category: Biochemistry Authors: Wilding M, Hong N, Spence M, Buckle AM, Jackson CJ Tags: Biochem Soc Trans Source Type: research

On fitness: how do mutations shape the biology of cancer?
Abstract The theory of evolution by natural selection shapes our understanding of the living world. While natural selection has given rise to all the intricacies of life on the planet, those responsible for treating cancer have a darker view of adaptation and selection. Revolutionary changes in DNA sequencing technology have allowed us to survey the complexities that constitute the cancer genome, while advances in genetic engineering are allowing us to functionally interrogate these alterations. These approaches are providing new insights into how mutations influence cancer biology. It is possible that with time, ...
Source: Biochemical Society Transactions - March 8, 2019 Category: Biochemistry Authors: Majewski IJ Tags: Biochem Soc Trans Source Type: research

The Escherichia coli multiple antibiotic resistance activator protein represses transcription of the lac operon.
Abstract In Escherichia coli, the marRAB operon is a determinant for antibiotic resistance. Such phenotypes require the encoded transcription factor MarA that activates efflux pump expression. To better understand all genes controlled by MarA, we recently mapped binding of the regulator across the E. coli genome. As expected, many MarA targets were adjacent to genes encoding stress response systems. Surprisingly, one MarA-binding site overlapped the lac operon regulatory region. Here, we show that MarA specifically targets this locus and can block transcription of the lac genes. Repression is mediated by binding o...
Source: Biochemical Society Transactions - March 8, 2019 Category: Biochemistry Authors: Lankester A, Ahmed S, Lamberte LE, Kettles RA, Grainger DC Tags: Biochem Soc Trans Source Type: research

Biological relevance of cell-in-cell in cancers.
Abstract Cell-in-cell (CIC) is a term used to describe the presence of one, usually living, cell inside another cell that is typically considered non-phagocytic. Examples of this include tumour cells inside tumour cells (homotypic), mesenchymal stem cells inside tumour cells (heterotypic) or immune cells inside tumour cells (heterotypic). CIC formation can occur in cell lines and in tissues and it has been most frequently observed during inflammation and in cancers. Over the past 10 years, many researchers have studied CIC structures and a few different models have been proposed through which they can be formed, i...
Source: Biochemical Society Transactions - March 8, 2019 Category: Biochemistry Authors: Mackay HL, Muller PAJ Tags: Biochem Soc Trans Source Type: research

Transcriptional noise and exaptation as sources for bacterial sRNAs.
Abstract Understanding how new genes originate and integrate into cellular networks is key to understanding evolution. Bacteria present unique opportunities for both the natural history and experimental study of gene origins, due to their large effective population sizes, rapid generation times, and ease of genetic manipulation. Bacterial small non-coding RNAs (sRNAs), in particular, many of which operate through a simple antisense regulatory logic, may serve as tractable models for exploring processes of gene origin and adaptation. Understanding how and on what timescales these regulatory molecules arise has impo...
Source: Biochemical Society Transactions - March 5, 2019 Category: Biochemistry Authors: Jose BR, Gardner PP, Barquist L Tags: Biochem Soc Trans Source Type: research

Membrane trafficking in osteoclasts and implications for osteoporosis.
Abstract Osteoclasts are large multinucleated cells exquisitely adapted to resorb bone matrix. Like other eukaryotes, osteoclasts possess an elaborate ensemble of intracellular organelles through which solutes, proteins and other macromolecules are trafficked to their target destinations via membrane-bound intermediaries. During bone resorption, membrane trafficking must be tightly regulated to sustain the structural and functional polarity of the osteoclasts' membrane domains. Of these, the ruffled border (RB) is most characteristic, functioning as the osteoclasts' secretory apparatus. This highly convoluted orga...
Source: Biochemical Society Transactions - March 5, 2019 Category: Biochemistry Authors: Ng PY, Brigitte Patricia Ribet A, Pavlos NJ Tags: Biochem Soc Trans Source Type: research

LRRK2 links genetic and sporadic Parkinson's disease.
Abstract The past two decades in research has revealed the importance of leucine-rich repeat kinase 2 (LRRK2) in both monogenic and sporadic forms of Parkinson's disease (PD). In families, mutations in LRRK2 can cause PD with age-dependent but variable penetrance and genome-wide association studies have found variants of the gene that are risk factors for sporadic PD. Functional studies have suggested that the common mechanism that links all disease-associated variants is that they increase LRRK2 kinase activity, albeit in different ways. Here, we will discuss the roles of LRRK2 in areas of inflammation and vesicu...
Source: Biochemical Society Transactions - March 5, 2019 Category: Biochemistry Authors: Kluss JH, Mamais A, Cookson MR Tags: Biochem Soc Trans Source Type: research

Caught in the act: LRRK2 in exosomes.
Abstract Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a frequent genetic cause of late-onset Parkinson's disease (PD) and a target for therapeutic approaches. LRRK2 protein can influence vesicle trafficking events in the cytosol, with action both in endosomal and lysosomal pathways in different types of cells. A subset of late endosomes harbor intraluminal vesicles that can be secreted into the extracellular milieu. These extracellular vesicles, called exosomes, package LRRK2 protein for transport outside the cell into easily accessed biofluids. Both the cytoplasmic complement of LRRK2 as well as...
Source: Biochemical Society Transactions - March 5, 2019 Category: Biochemistry Authors: Wang S, West AB Tags: Biochem Soc Trans Source Type: research

Structural studies of plasmin inhibition.
Abstract Plasminogen (Plg) is the zymogen form of the serine protease plasmin (Plm), and it plays a crucial role in fibrinolysis as well as wound healing, immunity, tissue remodeling and inflammation. Binding to the targets via the lysine-binding sites allows for Plg activation by plasminogen activators (PAs) present on the same target. Cellular uptake of fibrin degradation products leads to apoptosis, which represents one of the pathways for cross-talk between fibrinolysis and tissue remodeling. Therapeutic manipulation of Plm activity plays a vital role in the treatments of a range of diseases, whereas Plm inhib...
Source: Biochemical Society Transactions - March 5, 2019 Category: Biochemistry Authors: Wu G, Quek AJ, Caradoc-Davies TT, Ekkel SM, Mazzitelli B, Whisstock JC, Law RHP Tags: Biochem Soc Trans Source Type: research

Transcription in cyanobacteria: a distinctive machinery and putative mechanisms.
Abstract Transcription in cyanobacteria involves several fascinating features. Cyanobacteria comprise one of the very few groups in which no proofreading factors (Gre homologues) have been identified. Gre factors increase the efficiency of RNA cleavage, therefore helping to maintain the fidelity of the RNA transcript and assist in the resolution of stalled RNAPs to prevent genome damage. The vast majority of bacterial species encode at least one of these highly conserved factors and so their absence in cyanobacteria is intriguing. Additionally, the largest subunit of bacterial RNAP has undergone a split in cyanoba...
Source: Biochemical Society Transactions - March 5, 2019 Category: Biochemistry Authors: Riaz-Bradley A Tags: Biochem Soc Trans Source Type: research

Correction: Cryo-EM in drug discovery.
PMID: 30819927 [PubMed - in process] (Source: Biochemical Society Transactions)
Source: Biochemical Society Transactions - February 28, 2019 Category: Biochemistry Authors: Ceska T, Chung CW, Cooke R, Phillips C, Williams PA Tags: Biochem Soc Trans Source Type: research

The role of VPS4 in ESCRT-III polymer remodeling.
Abstract The endosomal sorting complex required for transport-III (ESCRT-III) and VPS4 catalyze a variety of membrane-remodeling processes in eukaryotes and archaea. Common to these processes is the dynamic recruitment of ESCRT-III proteins from the cytosol to the inner face of a membrane neck structure, their activation and filament formation inside or at the membrane neck and the subsequent or concomitant recruitment of the AAA-type ATPase VPS4. The dynamic assembly of ESCRT-III filaments and VPS4 on cellular membranes induces constriction of membrane necks with large diameters such as the cytokinetic midbody an...
Source: Biochemical Society Transactions - February 19, 2019 Category: Biochemistry Authors: Caillat C, Maity S, Miguet N, Roos WH, Weissenhorn W Tags: Biochem Soc Trans Source Type: research

Engineering of receptor-binding proteins in bacteriophages and phage tail-like bacteriocins.
ers Y Abstract Bacteriophages and phage tail-like bacteriocins (PTLBs) rely on receptor-binding proteins (RBPs) located in tail fibers or spikes for an initial and specific interaction with susceptible bacteria. Bacteriophages kill bacteria through a lytic, replicative cycle, whereas PTLBs kill the target through membrane depolarization in a single hit mechanism. Extensive efforts in the engineering of RBPs of both phages and PTLBs have been undertaken to obtain a greater understanding of the structural organization of RBPs. In addition, a major goal of engineering RBPs of phages and PTLBs is the production of ant...
Source: Biochemical Society Transactions - February 19, 2019 Category: Biochemistry Authors: Dams D, Brøndsted L, Drulis-Kawa Z, Briers Y Tags: Biochem Soc Trans Source Type: research

Coenzyme A: a protective thiol in bacterial antioxidant defence.
Abstract Coenzyme A (CoA) is an indispensable cofactor in all living organisms. It is synthesized in an evolutionarily conserved pathway by enzymatic conjugation of cysteine, pantothenate (Vitamin B5), and ATP. This unique chemical structure allows CoA to employ its highly reactive thiol group for diverse biochemical reactions. The involvement of the CoA thiol group in the production of metabolically active CoA thioesters (e.g. acetyl CoA, malonyl CoA, and HMG CoA) and activation of carbonyl-containing compounds has been extensively studied since the discovery of this cofactor in the middle of the last century. We...
Source: Biochemical Society Transactions - February 19, 2019 Category: Biochemistry Authors: Gout I Tags: Biochem Soc Trans Source Type: research

Antibiotic resistance in grass and soil.
Abstract Antibiotic resistance is currently one of the greatest threats to human health. The global overuse of antibiotics in human medicine and in agriculture has resulted in the proliferation and dissemination of a multitude of antibiotic resistance genes (ARGs). Despite a large proportion of antibiotics being used in agriculture, little is understood about how this may contribute to the overall antibiotic resistance crisis. The use of manure in agriculture is a traditional and widespread practice and is essential for returning nutrients to the soil; however, the impact of continuous manure application on the en...
Source: Biochemical Society Transactions - February 19, 2019 Category: Biochemistry Authors: Tyrrell C, Burgess CM, Brennan FP, Walsh F Tags: Biochem Soc Trans Source Type: research

It's all about the T: transcription termination in archaea.
Abstract One of the most fundamental biological processes driving all life on earth is transcription. The, at first glance, relatively simple cycle is divided into three stages: initiation at the promoter site, elongation throughout the open reading frame, and finally termination and product release at the terminator. In all three processes, motifs of the template DNA and protein factors of the transcription machinery including the multisubunit polymerase itself as well as a broad range of associated transcription factors work together and mutually influence each other. Despite several decades of research, this in...
Source: Biochemical Society Transactions - February 19, 2019 Category: Biochemistry Authors: Maier LK, Marchfelder A Tags: Biochem Soc Trans Source Type: research

The role of chromosome segregation and nuclear organisation in human subfertility.
Abstract Spermatogenesis is central to successful sexual reproduction, producing large numbers of haploid motile male gametes. Throughout this process, a series of equational and reductional chromosome segregation precedes radical repackaging of the haploid genome. Faithful chromosome segregation is thus crucial, as is an ordered spatio-temporal 'dance' of packing a large amount of chromatin into a very small space. Ergo, when the process goes wrong, this is associated with an improper chromosome number, nuclear position and/or chromatin damage in the sperm head. Generally, screening for overall DNA damage is rela...
Source: Biochemical Society Transactions - February 7, 2019 Category: Biochemistry Authors: Fowler KE, Mandawala AA, Griffin DK Tags: Biochem Soc Trans Source Type: research

Twenty years of Mediator complex structural studies.
ret V Abstract Mediator is a large multiprotein complex conserved in all eukaryotes that plays an essential role in transcriptional regulation. Mediator comprises 25 subunits in yeast and 30 subunits in humans that form three main modules and a separable four-subunit kinase module. For nearly 20 years, because of its size and complexity, Mediator has posed a formidable challenge to structural biologists. The first two-dimensional electron microscopy (EM) projection map of Mediator leading to the canonical view of its division in three topological modules named Head, Middle and Tail, was published in 1999. Within t...
Source: Biochemical Society Transactions - February 7, 2019 Category: Biochemistry Authors: Verger A, Monté D, Villeret V Tags: Biochem Soc Trans Source Type: research

Transcription initiation factor TBP: old friend new questions.
Abstract In all domains of life, the regulation of transcription by DNA-dependent RNA polymerases (RNAPs) is achieved at the level of initiation to a large extent. Whereas bacterial promoters are recognized by a σ-factor bound to the RNAP, a complex set of transcription factors that recognize specific promoter elements is employed by archaeal and eukaryotic RNAPs. These initiation factors are of particular interest since the regulation of transcription critically relies on initiation rates and thus formation of pre-initiation complexes. The most conserved initiation factor is the TATA-binding protein (TBP), ...
Source: Biochemical Society Transactions - February 1, 2019 Category: Biochemistry Authors: Kramm K, Engel C, Grohmann D Tags: Biochem Soc Trans Source Type: research

ADP-ribosylation and intracellular traffic: an emerging role for PARP enzymes.
Abstract ADP-ribosylation is an ancient and reversible post-translational modification (PTM) of proteins, in which the ADP-ribose moiety is transferred from NAD+ to target proteins by members of poly-ADP-ribosyl polymerase (PARP) family. The 17 members of this family have been involved in a variety of cellular functions, where their regulatory roles are exerted through the modification of specific substrates, whose identification is crucial to fully define the contribution of this PTM. Evidence of the role of the PARPs is now available both in the context of physiological processes and of cell responses to stress ...
Source: Biochemical Society Transactions - February 1, 2019 Category: Biochemistry Authors: Grimaldi G, Corda D Tags: Biochem Soc Trans Source Type: research

The demise of catalysis, but new functions arise: pseudoenzymes as the phoenixes of the protein world.
Abstract Pseudoenzymes are noncatalytic homologues of enzymes and are found in most enzyme families. Although lacking catalytic activity and sometimes referred to as 'dead' enzymes, they instead resemble phoenixes because the loss of a catalytic function during evolution was associated with the development of vital new functions. They are important in regulating the activity and location of catalytically active homologues, scaffolding the assembly of signaling complexes, and regulating transcription or translation. They are key actors in cell proliferation and differentiation, proteostasis, and many other biochemi...
Source: Biochemical Society Transactions - February 1, 2019 Category: Biochemistry Authors: Jeffery CJ Tags: Biochem Soc Trans Source Type: research

Emerging paradigms for PilZ domain-mediated C-di-GMP signaling.
Abstract PilZ domain-containing proteins constitute a large family of bacterial signaling proteins. As a widely distributed protein domain for the binding of the second messenger c-di-GMP, the canonical PilZ domain contains a set of motifs that define the binding site for c-di-GMP and an allosteric switch for propagating local conformational changes. Here, we summarize some new insights gathered from recent studies on the commonly occurring single-domain PilZ proteins, YcgR-like proteins and PilZ domain-containing cellulose synthases. The studies collectively illuminate how PilZ domains function as cis- or trans-r...
Source: Biochemical Society Transactions - February 1, 2019 Category: Biochemistry Authors: Cheang QW, Xin L, Chea RYF, Liang ZX Tags: Biochem Soc Trans Source Type: research

Towards functional characterization of archaeal genomic dark matter.
Abstract A substantial fraction of archaeal genes, from ∼30% to as much as 80%, encode 'hypothetical' proteins or genomic 'dark matter'. Archaeal genomes typically contain a higher fraction of dark matter compared with bacterial genomes, primarily, because isolation and cultivation of most archaea in the laboratory, and accordingly, experimental characterization of archaeal genes, are difficult. In the present study, we present quantitative characteristics of the archaeal genomic dark matter and discuss comparative genomic approaches for functional prediction for 'hypothetical' proteins. We propose a list of t...
Source: Biochemical Society Transactions - February 1, 2019 Category: Biochemistry Authors: Makarova KS, Wolf YI, Koonin EV Tags: Biochem Soc Trans Source Type: research