Mechanism of plasmin generation by S100A10

2017 ◽  
Vol 117 (06) ◽  
pp. 1058-1071 ◽  
Author(s):  
Victoria A. Miller ◽  
Patricia A. Madureira ◽  
Ain Adilliah Kamaludin ◽  
Jeffrey Komar ◽  
Vandna Sharma ◽  
...  
Keyword(s):  
Cell Surface ◽  
Present Report ◽  
Fibrin Clot ◽  
New Paradigm ◽  
Mutant Proteins ◽  
Lysine Residues ◽  
A Cell ◽  
Kringle 2 ◽  
Established Role

SummaryPlasminogen (Pg) is cleaved to form plasmin by the action of specific plasminogen activators such as the tissue plasminogen activator (tPA). Although the interaction of tPA and Pg with the surface of the fibrin clot has been well characterised, their interaction with cell surface Pg receptors is poorly understood. S100A10 is a cell surface Pg receptor that plays a key role in cellular plasmin generation. In the present report, we have utilised domain-switched/deleted variants of tPA, truncated plasminogen variants and S100A10 site-directed mutant proteins to define the regions responsible for S100A10-dependent plasmin generation. In contrast to the established role of the finger domain of tPA in fibrin-stimulated plasmin generation, we show that the kringle-2 domain of tPA plays a key role in S100A10-dependent plasmin generation. The kringle-1 domain of plasminogen, indispensable for fibrin-binding, is also critical for S100A10-dependent plasmin generation. S100A10 retains activity after substitution or deletion of the carboxyl-terminal lysine suggesting that internal lysine residues contribute to its plasmin generating activity. These studies define a new paradigm for plasminogen activation by the plasminogen receptor, S100A10.

scholarly journals Neisseria gonorrhoeae Porin P1.B Induces Endosome Exocytosis and a Redistribution of Lamp1 to the Plasma Membrane

2002 ◽  
Vol 70 (11) ◽  
pp. 5965-5971 ◽  
Author(s):  
Patricia Ayala ◽  
Brandi Vasquez ◽  
Lee Wetzler ◽  
Magdalene So
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Cell Surface ◽  
Neisseria Gonorrhoeae ◽  
Bacterial Infection ◽  
Immunoglobulin A ◽  
Late Endosomes ◽  
A Cell ◽  
Iga Protease

ABSTRACT The immunoglobulin A (IgA) protease secreted by pathogenic Neisseria spp. cleaves Lamp1, thereby altering lysosomes in a cell and promoting bacterial intracellular survival. We sought to determine how the IgA protease gains access to cellular Lamp1 in order to better understand the role of this cleavage event in bacterial infection. In a previous report, we demonstrated that the pilus-induced Ca2+ transient triggers lysosome exocytosis in human epithelial cells. This, in turn, increases the level of Lamp1 at the plasma membrane, where it can be cleaved by IgA protease. Here, we show that porin also induces a Ca2+ flux in epithelial cells. This transient is similar in nature to that observed in phagocytes exposed to porin. In contrast to the pilus-induced Ca2+ transient, the porin-induced event does not trigger lysosome exocytosis. Instead, it stimulates exocytosis of early and late endosomes and increases Lamp1 on the cell surface. These results indicate that Neisseria pili and porin perturb Lamp1 trafficking in epithelial cells by triggering separate and distinct Ca2+-dependent exocytic events, bringing Lamp1 to the cell surface, where it can be cleaved by IgA protease.

scholarly journals COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator?

2020 ◽  
pp. 107385842093903 ◽  
Author(s):  
Antonio Oliviero ◽  
Fernando de Castro ◽  
Francesca Coperchini ◽  
Luca Chiovato ◽  
Mario Rotondi
Keyword(s):  
Olfactory System ◽  
Distress Syndrome ◽  
Present Report ◽  
Subsequent Development ◽  
Common Denominator ◽  
The World ◽  
The Common ◽  
Established Role ◽  
Physiological Peculiarity

COVID-19 is an ongoing viral pandemic that emerged from East Asia and quickly spread to the rest of the world. SARS-CoV-2 is the virus causing COVID-19. Acute respiratory distress syndrome (ARDS) is definitely one of the main clinically relevant consequences in patients with COVID-19. Starting from the earliest reports of the COVID-19 pandemic, two peculiar neurological manifestations (namely, hyposmia/anosmia and dysgeusia) were reported in a relevant proportion of patients infected by SARS-CoV-2. At present, the physiopathologic mechanisms accounting for the onset of these symptoms are not yet clarified. CXCL10 is a pro-inflammatory chemokine with a well-established role in the COVID-19-related cytokine storm and in subsequent development of ARDS. CXCL10 is also known to be involved in coronavirus-induced demyelination. On these bases, a role for CXCL10 as the common denominator between pulmonary and olfactory dysfunctions could be envisaged. The aim of the present report will be to hypothesize a role for CXCL10 in COVID-19 olfactory dysfunctions. Previous evidences supporting our hypothesis, with special emphasis to the role of CXCL10 in coronavirus-induced demyelination, the anatomical and physiological peculiarity of the olfactory system, and the available data supporting their link during COVID-19 infections, will be overviewed.

scholarly journals Genetic Characterization of a Cell Envelope-Associated Proteinase from Lactobacillus helveticus CNRZ32

1999 ◽  
Vol 181 (15) ◽  
pp. 4592-4597 ◽  
Author(s):  
Jeffrey A. Pederson ◽  
Gerald J. Mileski ◽  
Bart C. Weimer ◽  
James L. Steele
Keyword(s):  
Cell Surface ◽  
Deletion Mutant ◽  
Cell Envelope ◽  
Physiological Role ◽  
Lactobacillus Helveticus ◽  
Whole Cells ◽  
A Cell ◽  
Hydrolysis Of

ABSTRACT A cell envelope-associated proteinase gene (prtH) was identified in Lactobacillus helveticus CNRZ32. TheprtH gene encodes a protein of 1,849 amino acids and with a predicted molecular mass of 204 kDa. The deduced amino acid sequence of the prtH product has significant identity (45%) to that of the lactococcal PrtP proteinases. Southern blot analysis indicates thatprtH is not broadly distributed within L. helveticus. A prtH deletion mutant of CNRZ32 was constructed to evaluate the physiological role of PrtH. PrtH is not required for rapid growth or fast acid production in milk by CNRZ32. Cell surface proteinase activity and specificity were determined by hydrolysis of αs1-casein fragment 1-23 by whole cells. A comparison of CNRZ32 and its prtH deletion mutant indicates that CNRZ32 has at least two cell surface proteinases that differ in substrate specificity.

Phyllotaxis Turns over a New Leaf – A Review

2019 ◽  
Author(s):  
Derek T Lamport ◽  
Li Tan ◽  
Michael Held ◽  
Marcia Kieliszewski
Keyword(s):  
Cell Surface ◽  
Calcium Binding ◽  
Wall Stress ◽  
Protein Chemistry ◽  
Computer Prediction ◽  
Cell Wall Stress ◽  
A Cell ◽  
Ancient Problem ◽  
General Explanation

Sixty years ago in the lab adjacent to Fred Sanger (1958 Nobel Prize for protein chemistry), I discovered the cell surface hydroxyproline-rich glycoproteins. Nature keeps some of her secrets longer than others. It has taken many years to dissect the molecular function and biological role of extensins and arabinogalactan proteins (AGPs). Extensins template the formation of new cell walls. AGPs remained baffling and enigmatic until a Eureka moment when computer prediction of AGP calcium binding depicted paired glucuronic acid residues and thus the likely role of a cell surface AGP-Ca2+capacitor: In conjunction with the auxin-activated proton pump that releases bound Ca2+ it led us to formulate the Hechtian Growth Oscillator as A Global Paradigm with a pivotal role in Ca2+ homeostasis. The ramifications are profound. They cannot be shrugged off with sceptical disdain but demand critical reappraisal of current dogma. Phyllotaxis is an ancient problem; it involves an essential role for auxin and the auxin efflux “PIN” proteins together with mechanotransduction of stress-strain as phyllotactic determinants. However, a general explanation remains elusive despite much effort, particularly by mathematicians. Here we propose a novel biochemical algorithm: Hechtian oscillator transduction of cell wall stress generates phyllotactic patterns quite independent of a mathematical approach. Plants simply use different rules and follow a different route.

Both lysine-clusters of the NH2-terminal prion-protein fragment PrP23-110 are essential for t-PA mediated plasminogen activation

2004 ◽  
Vol 91 (03) ◽  
pp. 465-472 ◽  
Author(s):  
Guido Epple ◽  
Kristina Langfeld ◽  
Michael Baier ◽  
Hermann-Georg Holzhütter ◽  
Eckart Köttgen ◽  
...  
Keyword(s):  
Prion Protein ◽  
Plasmon Resonance ◽  
Cellular Prion Protein ◽  
Plasminogen Activation ◽  
Protein Fragment ◽  
Chip Surface ◽  
Mutant Proteins ◽  
Lysine Residues ◽  
Binding Curves

SummaryWe have recently shown that the NH2-terminal fragment (PrP23-110) of the human cellular prion protein (PrPc) stimulates t-PA mediated plasminogen activation. PrP23-110 contains an N-terminal lysine cluster (LC1; K23, K24, K27) and a C-terminal one (LC2; K101, K104, K106, K110). To study their biological function we have substituted all lysine residues of each cluster by alanine and generated the recombinant PrP proteins PrP23110sLC1 and PrP23-110sLC2. The ability of the mutant proteins to stimulate plasminogen activation was assayed. We found that both lysine clusters are essential for t-PA mediated plasminogen activation. We further studied the binding of soluble PrP23110 to immobilized t-PA or plasminogen using surface plasmon resonance. The recorded binding curves could not be modeled by classical 1:1 binding kinetics suggesting oligomerisation of PrP23-110. Further plasmon resonance studies show that indeed PrP23-110 binds to itself and that glycosaminoglycans modify this interaction. Binding of t-PA or plasminogen to PrP23-110 was no longer influenced by glycosaminoglycans when PrP23-110 was immobilized on the chip surface. Thus a possible role of heparin as a cofactor in the stimulation of plasminogen activation by t-PA could be the generation of a PrP23-110 form with both lysine clusters accessible for binding of t-PA and plasminogen.

scholarly journals Structure of the human marker of self 5-transmembrane receptor CD47

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gustavo Fenalti ◽  
Nicolas Villanueva ◽  
Mark Griffith ◽  
Barbra Pagarigan ◽  
Sirish Kaushik Lakkaraju ◽  
...  
Keyword(s):  
Cell Surface ◽  
Immune Recognition ◽  
Blocking Antibody ◽  
Loop Region ◽  
Macrophage Phagocytosis ◽  
Hydrogen Deuterium ◽  
A Cell ◽  
Tm Domain ◽  
Dynamics Simulations

AbstractCD47 is the only 5-transmembrane (5-TM) spanning receptor of the immune system. Its extracellular domain (ECD) is a cell surface marker of self that binds SIRPα and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα interaction. We present the crystal structure of full length CD47 bound to the function-blocking antibody B6H12. CD47 ECD is tethered to the TM domain via a six-residue peptide linker (114RVVSWF119) that forms an extended loop (SWF loop), with the fundamental role of inserting the side chains of W118 and F119 into the core of CD47 extracellular loop region (ECLR). Using hydrogen-deuterium exchange and molecular dynamics simulations we show that CD47’s ECLR architecture, comprised of two extracellular loops and the SWF loop, creates a molecular environment stabilizing the ECD for presentation on the cell surface. These findings provide insights into CD47 immune recognition, signaling and therapeutic intervention.

scholarly journals Teratocarcinoma stem cell adhesion: the role of divalent cations and a cell surface lectin.

1983 ◽  
Vol 96 (6) ◽  
pp. 1532-1537 ◽  
Author(s):  
L B Grabel ◽  
M S Singer ◽  
G R Martin ◽  
S D Rosen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Adhesion ◽  
Cell Surface ◽  
Divalent Cations ◽  
Intercellular Adhesion ◽  
The Other ◽  
Calcium Dependent ◽  
A Cell

We describe two additive systems of intercellular adhesion in teratocarcinoma stem cells (Nulli cell line). One component is divalent cation-dependent (Ca++ or Mg++) and the other involves a cell surface fucan/mannan-specific lectin, previously identified on stem cells by an erythrocyte rosetting assay. The existence of these two systems is inferred from the observation that reaggregation of stem cells was partially inhibited by the removal of divalent cations or by the presence of lectin inhibitors such as fucoidan, but reaggregation was completely blocked when the two conditions were combined. Our results are related to recent work describing a calcium-dependent system of intercellular adhesion in teratocarcinoma stem cells.

scholarly journals HuR up-regulates cell surface PD-L1 via stabilizing CMTM6 transcript in cancer

Oncogene ◽  
2021 ◽  
Vol 40 (12) ◽  
pp. 2230-2242
Author(s):  
Yanbin Liu ◽  
Xingzhi Li ◽  
Hui Zhang ◽  
Mingming Zhang ◽  
Yanli Wei
Keyword(s):  
Cell Surface ◽  
Immune Responses ◽  
Cancer Cells ◽  
Immune Suppression ◽  
Specific Inhibitor ◽  
Direct Association ◽  
Hu Antigen R ◽  
Established Role

AbstractDespite the well-established role of CMTM6 in the stabilization of cell surface PD-L1 in cancer cells, the mechanisms underlying CMTM6 expression and regulation are still largely unknown. Here we unexpectedly find a strikingly positive correlation between CMTM6 and Hu-Antigen R (HuR) expression in most types of cancer. Mechanistically, we elucidate HuR stabilizes CMTM6 mRNA via direct association with AU-rich elements (AREs) in its 3′UTR and predominantly up-regulates CMTM6, which is readily abolished by HuR-specific inhibitor, MS-444. Phenotypically, we notice abundant cell surface PD-L1 in HuR-high cancer cells, which significantly inhibits immune activation of co-cultured T cells as indicated by IL-2 production. Treatment with MS-444 completely relieves immune suppression imposed by HuR-overexpression and further stimulates immune responses. Ectopic HuR accelerates allograft tumor progression in vivo, which is greatly compromised by simultaneous administration with MS-444. Our study uncovers a novel mechanism in control of CMTM6 and therefore PD-L1 expression, and suggests the potential of combining HuR inhibitor with PD-1/PD-L1 antibodies for cancer immunotherapy.

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