scholarly journals Are specialised ABC transporters responsible for the circularisation of type I circular bacteriocins?

2020 ◽  
Author(s):  
Ben Vezina ◽  
Bernd H. A. Rehm ◽  
Andrew T. Smith
Keyword(s):  
Abc Transporters ◽  
Signal Sequence ◽  
Peptide Bond ◽  
Type I ◽  
Sequence Alignments ◽  
Membrane Pores ◽  
Ph Tolerance ◽  
Proteolytic Stability ◽  
Helical Proteins ◽  
Thermodynamic Feasibility

AbstractCircular bacteriocins are relatively stable, antimicrobial proteins produced by a range of Gram-positive bacteria and are circularised by a peptide bond between the N and C termini. They are compact, basic, α-helical proteins which are hydrophobic in nature and assemble to form Na+ or H+ membrane pores. Circularisation contributes to a stable protein structure with enhanced thermostability, pH tolerance, and proteolytic stability. Secretion of active bacteriocin requires a multi-gene cluster than enables production, self-immunity and secretion with a putative ATP-binding cassette (ABC) transporter playing a major role. However the mechanism of circularisation is not known.By analysing sequence alignments and structural predictions for the specialised ABC transporters of known circular bacteriocins and comparing them with more conventional ABC transporters, a mechanism for bacteriocin circularisation can be proposed. The additional conserved proteolytic domains of these ABC transporters are likely to be sedolisins or serine-carboxyl endopeptidases which firstly remove the signal sequence before coupling this directly to ligation of the N and C termini prior, probably via an enzyme bound acyl intermediate, prior to an ATP dependent translocation which ensures thermodynamic feasibility. We propose that circular bacteriocins are processed and circularised in this way, via their own specialised ABC transporters.

scholarly journals Positive natural selection in primate genes of the type I interferon response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena N. Judd ◽  
Alison R. Gilchrist ◽  
Nicholas R. Meyerson ◽  
Sara L. Sawyer
Keyword(s):  
Natural Selection ◽  
Positive Selection ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Interferon Stimulated Genes ◽  
Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

scholarly journals Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents

2020 ◽  
Vol 71 (4) ◽  
pp. 285-299
Author(s):  
Ana Matošević ◽  
Anita Bosak
Keyword(s):  
Peptide Bond ◽  
Structural Motif ◽  
Target Interaction ◽  
Modern Drug ◽  
First Pass Metabolism ◽  
First Pass ◽  
Functional Part ◽  
Proteolytic Stability ◽  
Carbamate Group ◽  
Pass Metabolism

AbstractDue to their very good chemical and proteolytic stability, ability to penetrate cell membranes, and resemblance to a peptide bond, carbamate derivatives have received much attention in recent years and got an important role in modern drug discovery and medicinal chemistry. Today, carbamates make structural and/or functional part of many drugs and prodrugs approved and marketed for the treatment of various diseases such as cancer, epilepsy, hepatitis C, HIV infection, and Alzheimer’s disease. In drugs they can play a role in drug-target interaction or improve the biological activity of parent molecules. In prodrugs they are mainly used to delay first-pass metabolism and enhance the bioavailability and effectiveness of compounds. This brief review takes a look at the properties and use of carbamates in various fields of medicine and provides quick insights into the mechanisms of action for some of them.

scholarly journals A hydroxamic acid–methacrylated collagen conjugate for the modulation of inflammation-related MMP upregulation

2018 ◽  
Vol 6 (22) ◽  
pp. 3703-3715 ◽  
Author(s):  
He Liang ◽  
Stephen J. Russell ◽  
David J. Wood ◽  
Giuseppe Tronci
Keyword(s):  
Hydroxamic Acid ◽  
Type I Collagen ◽  
Type I ◽  
Covalent Coupling ◽  
Proteolytic Stability

The selective covalent coupling of hydroxamic acid functions on to methacrylated type I collagen led to UV-cured networks with inherent MMP-modulating capability and enhanced proteolytic stability.

scholarly journals Intracellular processing and transport of NH2-terminally truncated forms of a hemagglutinin-neuraminidase type II glycoprotein.

1990 ◽  
Vol 111 (1) ◽  
pp. 31-44 ◽  
Author(s):  
M K Spriggs ◽  
P L Collins
Keyword(s):  
Signal Sequence ◽  
Active Form ◽  
Cytoplasmic Domain ◽  
Biologically Active ◽  
Membrane Insertion ◽  
Type I ◽  
Type Ii ◽  
Membrane Anchor ◽  
Amino Terminal ◽  
Signal Anchor

Six amino-terminal deletion mutants of the NH2-terminally anchored (type II orientation) hemagglutinin-neuraminidase (HN) protein of parainfluenza virus type 3 were expressed in tissue culture by recombinant SV-40 viruses. The mutations consisted of progressive deletions of the cytoplasmic domain and, in some cases, of the hydrophobic signal/anchor. Three activities were dissociated for the signal/anchor: membrane insertion, translocation, and anchoring/transport. HN protein lacking the entire cytoplasmic tail was inserted efficiently into the membrane of the endoplasmic reticulum but was translocated inefficiently into the lumen. However, the small amounts that were successfully translocated appeared to be processed subsequently in a manner indistinguishable from that of parental HN. Thus, the cytoplasmic domain was not required for maturation of this type II glycoprotein. Progressive deletions into the membrane anchor restored efficient translocation, indicating that the NH2-terminal 44 amino acids were fully dispensable for membrane insertion and translocation and that a 10-amino acid hydrophobic signal sequence was sufficient for both activities. These latter HN molecules appeared to be folded authentically as assayed by hemagglutination activity, reactivity with a conformation-specific antiserum, correct formation of intramolecular disulfide bonds, and homooligomerization. However, most (85-90%) of these molecules accumulated in the ER. This showed that folding and oligomerization into a biologically active form, which presumably represents a virion spike, occurs essentially to completion within that compartment but is not sufficient for efficient transport through the exocytotic pathway. Protein transport also appeared to depend on the structure of the membrane anchor. These latter mutants were not stably integrated in the membrane, and the small proportion (10-15%) that was processed through the exocytotic pathway was secreted. The maturation steps and some of the effects of mutations described here for a type II glycoprotein resemble previous observations for prototypic type I glycoproteins and are indicative of close similarities in these processes for proteins of both membrane orientations.

scholarly journals Transient translocation of the cytoplasmic (endo) domain of a type I membrane glycoprotein into cellular membranes.

1993 ◽  
Vol 120 (4) ◽  
pp. 877-883 ◽  
Author(s):  
N Liu ◽  
D T Brown
Keyword(s):  
Amino Acids ◽  
Membrane Protein ◽  
Signal Sequence ◽  
Attachment Site ◽  
Integral Membrane Protein ◽  
Carboxyl Terminus ◽  
Type I ◽  
E2 Glycoprotein ◽  
Typical Type ◽  
Membrane Spanning

The E2 glycoprotein of the alphavirus Sindbis is a typical type I membrane protein with a single membrane spanning domain and a cytoplasmic tail (endo domain) containing 33 amino acids. The carboxyl terminal domain of the tail has been implicated as (a) attachment site for nucleocapsid protein, and (b) signal sequence for integration of the other alpha-virus membrane proteins 6K and E1. These two functions require that the carboxyl terminus be exposed in the cell cytoplasm (a) and exposed in the lumen of the endoplasmic reticulum (b). We have investigated the orientation of this glycoprotein domain with respect to cell membranes by substituting a tyrosine for the normally occurring serine, four amino acids upstream of the carboxyl terminus. Using radioiodination of this tyrosine as an indication of the exposure of the glycoprotein tail, we have provided evidence that this domain is initially translocated into a membrane and is returned to the cytoplasm after export from the ER. This is the first demonstration of such a transient translocation of a single domain of an integral membrane protein and this rearrangement explains some important aspects of alphavirus assembly.

scholarly journals Evidence for a Role of the Adenosine 5′-Triphosphate-Binding Cassette Transporter A1 in the Externalization of Annexin I from Pituitary Folliculo-Stellate Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 1062-1073 ◽  
Author(s):  
Lee P. Chapman ◽  
Matthew J. Epton ◽  
Julia C. Buckingham ◽  
John F. Morris ◽  
Helen C. Christian
Keyword(s):  
Abc Transporters ◽  
Anterior Pituitary ◽  
Signal Sequence ◽  
Atp Binding ◽  
Annexin I ◽  
Adenocarcinoma Cells ◽  
Inhibitory Feedback ◽  
Immunofluorescence Labeling ◽  
Atp Binding Cassette

Annexin 1 (ANXA1) has a well-demonstrated role in early delayed inhibitory feedback of glucocorticoids in the pituitary. ANXA1 is located in folliculo-stellate (FS) cells, and glucocorticoids act on these cells to externalize and stimulate the synthesis of ANXA1. However, ANXA1 lacks a signal sequence so the mechanism by which ANXA1 is externalized from FS cells was unknown and has been investigated. The ATP-binding cassette (ABC) transporters are a large group of transporters with varied roles that include the externalization of proteins. Glucocorticoid-induced externalization of ANXA1 from an FS cell line (TtT/GF) and rat anterior pituitary was blocked by glyburide, which inhibits ABC transporters. Glyburide also blocked the glucocorticoid inhibition of forskolin-stimulated ACTH release from pituitary tissue in vitro. RT-PCR revealed mRNA and Western blotting demonstrated protein for the ATP binding cassette A1 (ABCA1) transporter in mouse FS, TtT/GF, and A549 lung adenocarcinoma cells from which glucocorticoids also induce externalization of ANXA1. In TtT/GF cells, immunofluorescence labeling revealed a near total colocalization of cell surface ANXA1 and ABCA1. We conclude that ANXA1, which mediates the early delayed feedback of glucocorticoids in the anterior pituitary, is externalized from FS cells by an ABC transporter and that the ABCA1 transporter is a likely candidate.

scholarly journals Molecular Determinants of Substrate Selectivity of a Pneumococcal Rgg-Regulated Peptidase-Containing ABC Transporter

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Charles Y. Wang ◽  
Jennifer S. Medlin ◽  
Don R. Nguyen ◽  
W. Miguel Disbennett ◽  
Suzanne Dawid
Keyword(s):  
Streptococcus Pneumoniae ◽  
Abc Transporters ◽  
Signal Sequence ◽  
Substrate Recognition ◽  
Substrate Selectivity ◽  
Nasopharyngeal Colonization ◽  
Competitive Fitness ◽  
Content Type ◽  
Fitness Advantage ◽  
Molecular Determinants

ABSTRACT Peptidase-containing ABC transporters (PCATs) are a widely distributed family of transporters which secrete double-glycine (GG) peptides. In the opportunistic pathogen Streptococcus pneumoniae (pneumococcus), the PCATs ComAB and BlpAB have been shown to secrete quorum-sensing pheromones and bacteriocins related to the competence and pneumocin pathways. Here, we describe another pneumococcal PCAT, RtgAB, encoded by the rtg locus and found intact in 17% of strains. The Rgg/SHP-like quorum-sensing system RtgR/S, which uses a peptide pheromone with a distinctive Trp-X-Trp motif, regulates expression of the rtg locus and provides a competitive fitness advantage in a mouse model of nasopharyngeal colonization. RtgAB secretes a set of coregulated rtg GG peptides. ComAB and BlpAB, which share a substrate pool, do not secrete the rtg GG peptides. Similarly, RtgAB does not efficiently secrete ComAB/BlpAB substrates. We examined the molecular determinants of substrate selectivity between ComAB, BlpAB, and RtgAB and found that the GG peptide signal sequences contain all the information necessary to direct secretion through specific transporters. Secretion through ComAB and BlpAB depends largely on the identity of four conserved hydrophobic signal sequence residues previously implicated in substrate recognition by PCATs. In contrast, a motif situated at the N-terminal end of the signal sequence, found only in rtg GG peptides, directs secretion through RtgAB. These findings illustrate the complexity in predicting substrate-PCAT pairings by demonstrating specificity that is not dictated solely by signal sequence residues previously implicated in substrate recognition. IMPORTANCE The export of peptides from the cell is a fundamental process carried out by all bacteria. One method of bacterial peptide export relies on a family of transporters called peptidase-containing ABC transporters (PCATs). PCATs export so-called GG peptides which carry out diverse functions, including cell-to-cell communication and interbacterial competition. In this work, we describe a PCAT-encoding genetic locus, rtg, in the pathogen Streptococcus pneumoniae (pneumococcus). The rtg locus is linked to increased competitive fitness advantage in a mouse model of nasopharyngeal colonization. We also describe how the rtg PCAT preferentially secretes a set of coregulated GG peptides but not GG peptides secreted by other pneumococcal PCATs. These findings illuminate a relatively understudied part of PCAT biology: how these transporters discriminate between different subsets of GG peptides. Ultimately, expanding our knowledge of PCATs will advance our understanding of the many microbial processes dependent on these transporters.

scholarly journals Phenotypic and Gene Expression Changes among Clonal Type I Strains of Toxoplasma gondii

2009 ◽  
Vol 8 (12) ◽  
pp. 1828-1836 ◽  
Author(s):  
Asis Khan ◽  
Michael S. Behnke ◽  
Ildiko R. Dunay ◽  
Michael W. White ◽  
L. David Sibley
Keyword(s):  
Gene Expression ◽  
Toxoplasma Gondii ◽  
Abc Transporters ◽  
Type I ◽  
Clonal Line ◽  
Clonal Type ◽  
Time Period ◽  
Natural Isolates

ABSTRACT Toxoplasma gondii has an unusual population structure consisting of three clonal lineages that predominate in North America and Europe. This simple pattern has encouraged the use of only a few laboratory isolates that are representative of each lineage. Principle among these is the type I RH strain, originally isolated from a child with encephalitis some 70 years ago. Comparison of different passages of the RH strain that have been propagated differently over the intervening time period revealed that the commonly used clonal line called RH-ERP was not representative of natural isolates of the type I lineage. Notably, RH-ERP formed much larger plaques than other type 1 strains, including a separate, earlier derived isolate of the RH strain. The RH-ERP variant also showed enhanced extracellular survival, faster growth, and decreased differentiation compared to the prototype type I strain GT1. Comparison of gene expression differences in the RH-ERP line revealed that several ABC transporters were upregulated, which may provide a growth advantage in vitro. These findings illustrate that dramatic phenotypic changes can arise in laboratory strains, emphasizing the need for comparison with recent clinical isolates.

scholarly journals AMIGO, a transmembrane protein implicated in axon tract development, defines a novel protein family with leucine-rich repeats

2003 ◽  
Vol 160 (6) ◽  
pp. 963-973 ◽  
Author(s):  
Juha Kuja-Panula ◽  
Marjaana Kiiltomäki ◽  
Takashi Yamashiro ◽  
Ari Rouhiainen ◽  
Heikki Rauvala
Keyword(s):  
Hippocampal Neurons ◽  
Transmembrane Domain ◽  
Signal Sequence ◽  
Transmembrane Protein ◽  
Protein Family ◽  
Type I ◽  
Fiber Tracts ◽  
Neuronal Tissues ◽  
Immunoglobulin Domain ◽  
Leucine Rich Repeats

Ordered differential display identified a novel sequence induced in neurons by the neurite-promoting protein amphoterin. We named this gene amphoterin-induced gene and ORF (AMIGO), and also cloned two other novel genes homologous to AMIGO (AMIGO2 and AMIGO3). Together, these three AMIGOs form a novel family of genes coding for type I transmembrane proteins which contain a signal sequence for secretion and a transmembrane domain. The deduced extracellular parts of the AMIGOs contain six leucine-rich repeats (LRRs) flanked by cysteine-rich LRR NH2- and COOH-terminal domains and by one immunoglobulin domain close to the transmembrane region. A substrate-bound form of the recombinant AMIGO ectodomain promoted prominent neurite extension in hippocampal neurons, and in solution, the same AMIGO ectodomain inhibited fasciculation of neurites. A homophilic and heterophilic binding mechanism is shown between the members of the AMIGO family. Our results suggest that the members of the AMIGO protein family are novel cell adhesion molecules among which AMIGO is specifically expressed on fiber tracts of neuronal tissues and participates in their formation.

scholarly journals Regional Blood—Brain Glucose Transfer in the Rat: A Novel Double-Membrane Kinetic Analysis

1986 ◽  
Vol 6 (3) ◽  
pp. 305-314 ◽  
Author(s):  
Vincent J. Cunningham ◽  
Richard J. Hargreaves ◽  
David Pelling ◽  
Stephen R. Moorhouse
Keyword(s):  
Endothelial Cell ◽  
Type I ◽  
Type Ii ◽  
Glucose Content ◽  
Brain Glucose ◽  
Glucose Transfer ◽  
Membrane Pores ◽  
Blood Brain ◽  
Anaesthetized Rats ◽  
Glucose Phosphorylation

Regional blood–brain glucose transfer was studied in pentobarbitone-anaesthetized rats using a programmed intravenous infusion technique that maintained steady levels of unlabeled (up to 55 m M) and tracer d-glucose in the circulating plasma. Regional cerebral blood flow, glucose phosphorylation rate, and tissue glucose content were also measured under comparable conditions. Data were analysed in terms of irreversible Michaelis–Menten kinetics assuming independent influx and efflux (Type I) and reversible Michaelis–Menten kinetics (Type II) across both the luminal and the abluminal membranes of the endothelial cell. The latter analysis corresponds to simple stereospecific membrane pores. The mathematical model allowed for changes in tissue glucose content and back-diffusion of tracer during the experiments. Type I analyses gave Kt values of ∼6.6 m M, whereas those by Type II were consistently lower. Interregional differences were not significant using either scheme. Comparison of Type II with Type I analyses revealed a possible explanation for discrepancies in the estimates of nonsaturable glucose transfer by different methods and highlighted the importance of tissue glucose measurements in studies of unidirectional glucose influx. Since the experimental data may be described equally well by either scheme and some interaction between influx and efflux across the endothelial cell might be expected, consideration of this alternative approach is suggested.

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