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Molecular Microbiology May 2020The twin-arginine protein transport (Tat pathway) is found in prokaryotes and plant organelles and transports folded proteins across membranes. Targeting of substrates... (Review)
Review
The twin-arginine protein transport (Tat pathway) is found in prokaryotes and plant organelles and transports folded proteins across membranes. Targeting of substrates to the Tat system is mediated by the presence of an N-terminal signal sequence containing a highly conserved twin-arginine motif. The Tat machinery comprises membrane proteins from the TatA and TatC families. Assembly of the Tat translocon is dynamic and is triggered by the interaction of a Tat substrate with the Tat receptor complex. This review will summarise recent advances in our understanding of Tat transport, focusing in particular on the roles played by Tat signal peptides in protein targeting and translocation.
Topics: Amino Acid Motifs; Bacterial Proteins; Cell Membrane; Escherichia coli Proteins; Membrane Transport Proteins; Protein Binding; Protein Conformation; Protein Sorting Signals; Protein Transport; Twin-Arginine-Translocation System
PubMed: 31971282
DOI: 10.1111/mmi.14461 -
Brain Research Bulletin Jul 2020Barriers are the hallmark of a healthy physiology, blood-brain barrier (BBB) being a tough nut to crack for most of the antigens and chemical substances. The presence of... (Review)
Review
Barriers are the hallmark of a healthy physiology, blood-brain barrier (BBB) being a tough nut to crack for most of the antigens and chemical substances. The presence of tight junctions plays a remarkable role in defending the brain from antigenic and pathogenic attacks. BBB constitutes a diverse assemblage of multiple physical and chemical barriers that judiciously restrict the flux of blood solutes into and out of the brain. Restrictions through the paracellular pathway and the tight junctions between intercellular clefts, together create well regulated metabolic and transport barricades, critical to brain pathophysiology. The brain being impermeable to many essential metabolites and nutrients regulates transportation via specialized transport systems across the endothelial abluminal and luminal membranes. The epithelial cells enveloping capillaries of the choroid plexus regulates the transport of complement, growth factors, hormones, microelements, peptides and trace elements into ventricles. Nerve terminals, microglia, and pericytes associated with the endothelium support barrier induction and function, ensuring an optimally stable ionic microenvironment that facilitates neurotransmission, orchestrated by multiple ion channels (Na, K Mg, Ca) and transporters. Brain pathology which can develop due to genetic mutations or secondary to other cerebrovascular, neurodegenerative diseases can cause aberration in the microvasculature of CNS which is the uniqueness of BBB. This can also alter BBB permeation and result in BBB breakdown and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The concluding section outlines contemporary trends in drug discovery, focusing on molecular determinants of BBB permeation and novel drug-delivery systems, such as dendrimers, liposomes, nanoparticles, nanogels, etc.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain; Humans; Membrane Proteins; Neurodegenerative Diseases; Pharmaceutical Preparations; Tight Junctions
PubMed: 32315731
DOI: 10.1016/j.brainresbull.2020.03.018 -
Food Research International (Ottawa,... Nov 2022This study aimed to investigate the absorption and transport of myofibrillar protein-bound N-(carboxymethyl)lysine (MP-bound CML) in Caco-2 cells after simulated...
This study aimed to investigate the absorption and transport of myofibrillar protein-bound N-(carboxymethyl)lysine (MP-bound CML) in Caco-2 cells after simulated gastrointestinal digestion. Four kinds of MP-bound CML hydrolysates with molecular weights (MWs) less than 1 kDa, 1-3 kDa, 3-5 kDa and greater than 5 kDa, were obtained by ultrafiltration; their absorption and transport were studied in Caco-2 cells. Peptide-bound CML in hydrolysates with MWs less than 1 kDa was absorbed by 6.58 % and might transport across Caco-2 cells monolayer through paracellular pathway; peptide-bound CML in hydrolysates with MWs 1-3 kDa was absorbed by 12.8 % and might transport across Caco-2 cells monolayer through paracellular pathway and transcytosis route; peptide-bound CML in hydrolysates with MWs 3-5 kDa was absorbed by 14.66 % and might be through active route via PepT-1 transport across Caco-2 cells monolayer; whereas protein-bound CML in hydrolysates with MWs greater than 5 kDa was only absorbed by 1.02 %, which was hardly transported into Caco-2 cells. In conclusion, MP-bound CML could be absorbed by 35.06 % into Caco-2 cells after simulated gastrointestinal digestion and is transported across Caco-2 cells through paracellular pathway, transcytosis route and active route via PepT-1.
Topics: Biological Transport; Caco-2 Cells; Digestion; Humans; Lysine; Organoplatinum Compounds; Peptides
PubMed: 36192990
DOI: 10.1016/j.foodres.2022.111870 -
Clinical and Translational Medicine May 2022Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti-cancer drugs are severely restricted from reaching the... (Review)
Review
Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti-cancer drugs are severely restricted from reaching the tumour site. Cell-penetrating peptides (CPPs) are typically made up of 5-30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti-cancer treatment strategies, serving as an excellent potential choice for oncology treatment. However, their drawbacks, such as the lack of cell specificity, short duration of action, poor stability in vivo, compatibility problems (i.e. immunogenicity), poor therapeutic efficacy and formation of unwanted metabolites, have limited their further application in cancer treatment. The cellular uptake mechanisms of CPPs involve mainly endocytosis and direct penetration, but still remain highly controversial in academia. The CPPs-based drug delivery strategy could be improved by clever design or chemical modifications to develop the next-generation CPPs with enhanced cell penetration capability, stability and selectivity. In addition, some recent advances in targeted cell penetration that involve CPPs provide some new ideas to optimise CPPs.
Topics: Biological Transport; Cell-Penetrating Peptides; Drug Delivery Systems; Endocytosis; Humans; Neoplasms; Tumor Microenvironment
PubMed: 35593206
DOI: 10.1002/ctm2.822 -
The Protein Journal Aug 2019The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from... (Review)
Review
The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from other protein transport systems with respect to two key features. Firstly, it accepts cargo proteins with an N-terminal signal peptide that carries the canonical twin-arginine motif, which is essential for transport. Second, the Tat system only accepts and translocates fully folded cargo proteins across the respective membrane. Here, we review the core essential features of folded protein transport via the bacterial Tat system, using the three-component TatABC system of Escherichia coli and the two-component TatAC systems of Bacillus subtilis as the main examples. In particular, we address features of twin-arginine signal peptides, the essential Tat components and how they assemble into different complexes, mechanistic features and energetics of Tat-dependent protein translocation, cytoplasmic chaperoning of Tat cargo proteins, and the remarkable proofreading capabilities of the Tat system. In doing so, we present the current state of our understanding of Tat-dependent protein translocation across biological membranes, which may serve as a lead for future investigations.
Topics: Arginine; Bacillus subtilis; Cell Membrane; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Protein Folding; Protein Sorting Signals; Protein Transport; SEC Translocation Channels; Twin-Arginine-Translocation System
PubMed: 31401776
DOI: 10.1007/s10930-019-09859-y -
Journal of Animal Physiology and Animal... Jan 2022Intestinal absorption of peptides is vital for the overall health and productivity of dairy cows. This study investigated the regulation, uptake and transport of...
Intestinal absorption of peptides is vital for the overall health and productivity of dairy cows. This study investigated the regulation, uptake and transport of dipeptides in bovine intestinal epithelial cells (BIECs). We also evaluated the effects of time, pH, concentration of the dipeptides, temperature, presence of diethylpyrocarbonate (DEPC)-an inhibitor of PepT1, and other dipeptides (Met-Met, Lys-Lys or Met-Lys), on the uptake and transport of Gly-Sar-FITC, which was a common fluorophore-labelled dipeptide. Under controlled experiments, BIECs were treated with 25 μM LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor) and 25 μM Perifosine (a protein kinase B (AKT) inhibitor). The subsequent expression of PepT1 in the BIECs was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. It was found that the uptake and transport of Gly-Sar-FITC were significant high at 37℃ than that at 4℃. The optimal pH for transport and uptake of Gly-Sar-FITC was 6.0-6.5, whereas the two properties decreased significantly in the presence of DEPC, Met-Met, Lys-Lys and Met-Lys (p < 0.05). The apical-to-basolateral transport was also found to be significantly higher than the reverse transport (p < 0.05). PI3K and AKT inhibitors were found to significantly suppress the expression of PepT1, thus impairing uptake and transport of Gly-Sar-FITC. Findings of this study thus suggest that the uptake and transport of Gly-Sar-FITC in BIECs are mediated by PepT1, and the PI3K/AKT signalling pathway regulates the absorption of small peptides.
Topics: Animals; Biological Transport; Caco-2 Cells; Cattle; Dipeptides; Epithelial Cells; Female; Humans; Peptide Transporter 1; Phosphatidylinositol 3-Kinases; Symporters
PubMed: 33834547
DOI: 10.1111/jpn.13546 -
Biomolecules Jan 2021Cell plasma membrane proteins are considered as gatekeepers of the cell and play a major role in regulating various processes. Transport proteins constitute a subclass... (Review)
Review
Cell plasma membrane proteins are considered as gatekeepers of the cell and play a major role in regulating various processes. Transport proteins constitute a subclass of cell plasma membrane proteins enabling the exchange of molecules and ions between the extracellular environment and the cytosol. A plethora of human pathologies are associated with the altered expression or dysfunction of cell plasma membrane transport proteins, making them interesting therapeutic drug targets. However, the search for therapeutics is challenging, since many drug candidates targeting cell plasma membrane proteins fail in (pre)clinical testing due to inadequate selectivity, specificity, potency or stability. These latter characteristics are met by nanobodies, which potentially renders them eligible therapeutics targeting cell plasma membrane proteins. Therefore, a therapeutic nanobody-based strategy seems a valid approach to target and modulate the activity of cell plasma membrane transport proteins. This review paper focuses on methodologies to generate cell plasma membrane transport protein-targeting nanobodies, and the advantages and pitfalls while generating these small antibody-derivatives, and discusses several therapeutic nanobodies directed towards transmembrane proteins, including channels and pores, adenosine triphosphate-powered pumps and porters.
Topics: Antigens; Cell Membrane; Humans; Membrane Transport Proteins; Models, Biological; Single-Domain Antibodies
PubMed: 33418902
DOI: 10.3390/biom11010063 -
Pflugers Archiv : European Journal of... Apr 2024Secretin is a key hormone of the intestinal phase of digestion which activates pancreatic, bile duct and Brunner gland HCO secretion. Recently, the secretin receptor... (Review)
Review
Secretin is a key hormone of the intestinal phase of digestion which activates pancreatic, bile duct and Brunner gland HCO secretion. Recently, the secretin receptor (SCTR) was also found in the basolateral membrane of the beta-intercalated cell (B-IC) of the collecting duct. Experimental addition of secretin triggers a pronounced activation of urinary HCO excretion, which is fully dependent on key functional proteins of the B-IC, namely apical pendrin and CFTR and the basolateral SCTR. Recent studies demonstrated that the SCTR knock-out mouse is unable to respond to an acute base load. Here, SCTR KO mice could not rapidly increase urine base excretion, developed prolonged metabolic alkalosis and exhibited marked compensatory hypoventilation. Here, we review the physiological effects of secretin with distinct focus on how secretin activates renal HCO excretion. We describe its new function as a hormone for HCO homeostasis.
Topics: Mice; Animals; Secretin; Cell Membrane; Sulfate Transporters; Biological Transport; Homeostasis; Bicarbonates
PubMed: 38221598
DOI: 10.1007/s00424-024-02906-3 -
Current Opinion in Plant Biology Aug 2022The nitrate and peptide transporter family (NPF) is one of the largest transporter families in the plant kingdom. The name of the family reflects the substrates (nitrate... (Review)
Review
The nitrate and peptide transporter family (NPF) is one of the largest transporter families in the plant kingdom. The name of the family reflects the substrates (nitrate and peptides) identified for the two founding members CHL1 and PTR2 from Arabidopsis thaliana almost 30 years ago. However, since then, the NPF has emerged as a hotspot for transporters with a wide range of crucial roles in plant specialized metabolism. Recent prominent examples include 1) controlling accumulation of antinutritional glucosinolates in Brassica seeds, 2) deposition of heat-stress tolerance flavonol diglucosides to pollen coats 3) production of anti-cancerous monoterpene indole alkaloid precursors in Catharanthus roseus and 4) detoxification of steroid glycoalkaloids in ripening tomatoes. In this review, we turn the spotlight on the emerging role of the NPF in plant specialized metabolism and its potential for improving crop traits through transport engineering.
Topics: Anion Transport Proteins; Arabidopsis; Gene Expression Regulation, Plant; Membrane Transport Proteins; Nitrates; Peptides; Plant Proteins; Plants
PubMed: 35709542
DOI: 10.1016/j.pbi.2022.102243 -
Chemical Communications (Cambridge,... Nov 2021Calixarenes are reportedly excellent activators that can remarkably improve the transport efficiencies of cell penetrating peptides. We employed eight calixarenes to...
Calixarenes are reportedly excellent activators that can remarkably improve the transport efficiencies of cell penetrating peptides. We employed eight calixarenes to systematically study the influence of structure on activation efficiency, which revealed that the scaffold, head group, and alkyl chain are all significant factors for activation efficiency by affecting affinities with the peptide and membrane.
Topics: Biological Transport; Calixarenes; Drug Evaluation, Preclinical; Humans; Molecular Structure; Peptides
PubMed: 34761762
DOI: 10.1039/d1cc05414g