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Olivier Spertini - One of the best experts on this subject based on the ideXlab platform.
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molecular basis of leukocyte rolling on psgl 1 predominant role of core 2 o glycans and of tyrosine sulfate residue 51
Journal of Biological Chemistry, 2003Co-Authors: Michael Pierre Bernimoulin, Xianlu Zeng, Claire Abbal, Sylvain Giraud, Manuel Martinez, Olivier Michielin, Marc Schapira, Olivier SpertiniAbstract:Abstract Interactions between the leukocyte adhesion receptor L-selectin and P-selectin glycoprotein ligand-1 play an important role in regulating the inflammatory response by mediating leukocyte tethering and rolling on adherent leukocytes. In this study, we have examined the effect of post-translational modifications of PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O-glycans for L-selectin binding. The functional importance of these modifications was determined by analyzing soluble L-selectin binding and leukocyte rolling on CHO cells expressing various glycoforms of PSGL-1 or mutant PSGL-1 targeted at N-terminal Thr or Tyr residues. Simultaneous expression of core-2 β1,6-N-acetylglucosaminyltransferase and fucosyltransferase VII was required for optimal L-selectin binding to PSGL-1. Substitution of Thr-57 by Ala but not of Thr-44, strongly decreased L-selectin binding and leukocyte rolling on PSGL-1. Substitution of Tyr by Phe revealed that PSGL-1 Tyr-51 plays a predominant role in mediating L-selectin binding and leukocyte rolling whereas Tyr-48 has a minor role, an observation that contrasts with the pattern seen for the interactions between PSGL-1 and P-selectin where Tyr-48 plays a key role. Molecular modeling analysis of L-selectin and P-selectin interactions with PSGL-1 further supported these observations. Additional experiments showed that core-2O-glycans attached to Thr-57 were also of critical importance in regulating the velocity and stability of leukocyte rolling. These observations pinpoint the structural characteristics of PSGL-1 that are required for optimal interactions with L-selectin and may be responsible for the specific kinetic and mechanical bond properties of the L-selectin-PSGL-1 adhesion receptor-counterreceptor pair.
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molecular basis of leukocyte rolling on psgl 1 predominant role of core 2 o glycans and of tyrosine sulfate residue 51
Journal of Biological Chemistry, 2003Co-Authors: Michael Pierre Bernimoulin, Xianlu Zeng, Claire Abbal, Sylvain Giraud, Manuel Martinez, Olivier Michielin, Marc Schapira, Olivier SpertiniAbstract:Interactions between the leukocyte adhesion receptor L-selectin and P-selectin glycoprotein ligand-1 play an important role in regulating the inflammatory response by mediating leukocyte tethering and rolling on adherent leukocytes. In this study, we have examined the effect of post-translational modifications of PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O-glycans for L-selectin binding. The functional importance of these modifications was determined by analyzing soluble L-selectin binding and leukocyte rolling on CHO cells expressing various glycoforms of PSGL-1 or mutant PSGL-1 targeted at N-terminal Thr or Tyr residues. Simultaneous expression of core-2 beta1,6-N-acetylglucosaminyltransferase and fucosyltransferase VII was required for optimal L-selectin binding to PSGL-1. Substitution of Thr-57 by Ala but not of Thr-44, strongly decreased L-selectin binding and leukocyte rolling on PSGL-1. Substitution of Tyr by Phe revealed that PSGL-1 Tyr-51 plays a predominant role in mediating L-selectin binding and leukocyte rolling whereas Tyr-48 has a minor role, an observation that contrasts with the pattern seen for the interactions between PSGL-1 and P-selectin where Tyr-48 plays a key role. Molecular modeling analysis of L-selectin and P-selectin interactions with PSGL-1 further supported these observations. Additional experiments showed that core-2 O-glycans attached to Thr-57 were also of critical importance in regulating the velocity and stability of leukocyte rolling. These observations pinpoint the structural characteristics of PSGL-1 that are required for optimal interactions with L-selectin and may be responsible for the specific kinetic and mechanical bond properties of the L-selectin-PSGL-1 adhesion receptor-counterreceptor pair.
Boris Macek - One of the best experts on this subject based on the ideXlab platform.
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ser thr tyr protein phosphorylation in the archaeon halobacterium salinarum a representative of the third domain of life
PLOS ONE, 2009Co-Authors: Michalis Aivaliotis, Florian Gnad, Matthias Mann, Boris Macek, Peter Reichelt, Dieter OesterheltAbstract:In the quest for the origin and evolution of protein phosphorylation, the major regulatory post-translational modification in eukaryotes, the members of archaea, the “third domain of life”, play a protagonistic role. A plethora of studies have demonstrated that archaeal proteins are subject to post-translational modification by covalent phosphorylation, but little is known concerning the identities of the proteins affected, the impact on their functionality, the physiological roles of archaeal protein phosphorylation/dephosphorylation, and the protein kinases/phosphatases involved. These limited studies led to the initial hypothesis that archaea, similarly to other prokaryotes, use mainly histidine/aspartate phosphorylation, in their two-component systems representing a paradigm of prokaryotic signal transduction, while eukaryotes mostly use Ser/Thr/Tyr phosphorylation for creating highly sophisticated regulatory networks. In antithesis to the above hypothesis, several studies showed that Ser/Thr/Tyr phosphorylation is also common in the bacterial cell, and here we present the first genome-wide phosphoproteomic analysis of the model organism of archaea, Halobacterium salinarum, proving the existence/conservation of Ser/Thr/Tyr phosphorylation in the “third domain” of life, allowing a better understanding of the origin and evolution of the so-called “Nature's premier” mechanism for regulating the functional properties of proteins.
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the ser thr tyr phosphoproteome of lactococcus lactis il1403 reveals multiply phosphorylated proteins
Proteomics, 2008Co-Authors: Boumediene Soufi, Florian Gnad, Peter Ruhdal Jensen, Dina Petranovic, Matthias Mann, Ivan Mijakovic, Boris MacekAbstract:Recent phosphoproteomics studies of several bacterial species have firmly established protein phosphorylation on Ser/Thr/Tyr residues as a PTM in bacteria. In particular, our recent reports on the Ser/Thr/Tyr phosphoproteomes of bacterial model organisms Bacillus subtilis and Escherichia coli detected over 100 phosphorylation events in each of the bacterial species. Here we extend our analyses to Lactococcus lactis, a lactic acid bacterium widely employed by the food industry, in which protein phosphorylation at Ser/Thr/Tyr residues was barely studied at all. Despite the lack of almost any prior evidence of Ser/Thr/Tyr protein phosphorylation in L. lactis, we identified a phosphoproteome of a size comparable to that of E. coli and B. subtilis, with 73 phosphorylation sites distributed over 63 different proteins. The presence of several multiply phosphorylated proteins, as well as over-representation of phosphothreonines seems to be the distinguishing features of the L. lactis phosphoproteome. Evolutionary comparison and the conservation of phosphorylation sites in different bacterial organisms indicate that a majority of the detected phosphorylation sites are species-specific, and therefore have probably co-evolved with the adaptation of the bacterial species to their present-day ecological niches.
Ellen A Walker - One of the best experts on this subject based on the ideXlab platform.
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potency differences ford phe cys tyr d trp arg thr pen thr nh2as an antagonist of peptide and alkaloid μ agonists in an antinociception assay
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Steven N Sterious, Ellen A WalkerAbstract:d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2(CTAP) is a peptide antagonist that demonstrates potent and selective affinity for μ-opioid receptors in radioligand binding assays and in vitro bioassays. However, previous studies indicate that CTAP may possess unusual pharmacology under certain conditions. Therefore, CTAP was evaluated as an antagonist of the antinociceptive effects of a range of structurally diverse high- and low-efficacy peptide and alkaloid opioid agonists and compared with the traditional antagonist naltrexone. Male Sprague-Dawley rats ( N = 227) were loosely restrained and the latency for tail withdrawal from 55°C water was measured. Morphine s.c. and i.c.v., buprenorphine s.c., etorphine s.c. and i.c.v., [ N -Me-Phe3,d-Pro4]-morphiceptin and [d-Ala2, N -Me-Phe4,Gly5-ol]-enkephalin produced antinociceptive effects. CTAP was at least 10-fold more potent than naltrexone as an antagonist of the antinociceptive effects of all five agonists. High doses of CTAP produced a noncompetitive antagonism of etorphine s.c. and morphine s.c. suggesting that CTAP may interact with additional opioid receptors in vivo or produce insurmountable antagonism at these doses. CTAP was approximately 300-fold more potent as an antagonist of DAMGO than the other agonists, indicating that CTAP may distinguish some peptide agonists such as DAMGO from other agonists based on binding interactions within the μ-opioid receptor or pharmacodynamic properties of these peptides. Naltrexone, however, administered by either s.c. or i.c.v. routes of administration was approximately equipotent as an antagonist of the antinociceptive effects of most agonists. Taken together, these data indicate that the peptide antagonist CTAP possesses a unique pharmacology unlike traditional opioid antagonists such as naltrexone.
Macdonald J Christie - One of the best experts on this subject based on the ideXlab platform.
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the mu opioid receptor antagonist d phe cys tyr d trp orn thr pen thr nh2 ctop but not d phe cys tyr d trp arg thr pen thr nh2 ctap produces a nonopioid receptor mediated increase in k conductance of rat locus ceruleus neurons
Molecular Pharmacology, 1996Co-Authors: Billy Chieng, Mark Connor, Macdonald J ChristieAbstract:The somatostatin analogues D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) have been used widely as selective antagonists of mu-opioid receptors. Actions of CTOP and CTAP on the membrane properties of rat locus ceruleus neurons were studied using intracellular recordings of membrane currents in superfused brain slices. CTOP increased a K+ conductance with an EC50 of 560 nM. The maximal conductance increase produced by CTOP (10 microM) was similar to that produced by high concentrations of the mu-opioid agonists D-Ala-Met-enkephalinglyol (1 microM) and Met-enkephalin (10 microM), as well as an alpha 2-adrenoceptor agonist (UK14304, 3 microM) and somatostatin (1 microM). The K+ current produced by CTOP was not antagonized by naloxone (1 microM), suggesting it was not mediated by mu-opioid receptors. The K+ currents induced by high concentrations of CTOP desensitized to 42% of the initial maximum after prolonged superfusion (t1/2 = 247 sec). In the presence of fully desensitized CTOP responses, somatostatin (1 microM) still produced near-maximal K+ currents; i.e., there was no cross-desensitization, which suggests that CTOP might act on a receptor distinct from somatostatin receptors. However, the converse did not apply; high concentrations of CTOP (30 microM) did not produce any additional current in the presence of desensitized somatostatin responses. No cross-desensitization was observed between CTOP (10-30 microM) and Met-enkephalin (30 microM) or nociceptin (3 microM) regardless of the order of drug application. Cyclo-(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr[Bzl], antagonized both somatostatin-(KD = 10 microM) and CTOP-(KD = 8 microM) induced K+ currents with similar potency. Concentrations of CTOP (100 nM) that produced a small K+ current partially antagonized the actions of Met-enkephalin (10 microM) on mu-opioid receptors. In contrast to CTOP, CTAP produced no K+ current at concentrations of 300 nM and 1 microM and little current at 10 microM. CTAP potently antagonized K+ currents produced by the mu-opioid receptor agonist D-Ala-Met-enkephalin-glyol, with an equilibrium dissociation constant of 4 nM (Schild analysis). CTAP did not antagonize K+ currents produced by CTOP or somatostatin. These results demonstrate that CTOP is a potent and efficacious agonist at nonopioid receptors, whereas CTAP is a potent mu-opioid receptor antagonist with little nonopioid agonist activity in rat locus ceruleus neurons. The receptor activated by CTOP has yet to be fully resolved but seems to be similar to the somatostatin type 2 receptor or perhaps to a receptor closely related to somatostatin or opioid receptors.
Michael Pierre Bernimoulin - One of the best experts on this subject based on the ideXlab platform.
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molecular basis of leukocyte rolling on psgl 1 predominant role of core 2 o glycans and of tyrosine sulfate residue 51
Journal of Biological Chemistry, 2003Co-Authors: Michael Pierre Bernimoulin, Xianlu Zeng, Claire Abbal, Sylvain Giraud, Manuel Martinez, Olivier Michielin, Marc Schapira, Olivier SpertiniAbstract:Abstract Interactions between the leukocyte adhesion receptor L-selectin and P-selectin glycoprotein ligand-1 play an important role in regulating the inflammatory response by mediating leukocyte tethering and rolling on adherent leukocytes. In this study, we have examined the effect of post-translational modifications of PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O-glycans for L-selectin binding. The functional importance of these modifications was determined by analyzing soluble L-selectin binding and leukocyte rolling on CHO cells expressing various glycoforms of PSGL-1 or mutant PSGL-1 targeted at N-terminal Thr or Tyr residues. Simultaneous expression of core-2 β1,6-N-acetylglucosaminyltransferase and fucosyltransferase VII was required for optimal L-selectin binding to PSGL-1. Substitution of Thr-57 by Ala but not of Thr-44, strongly decreased L-selectin binding and leukocyte rolling on PSGL-1. Substitution of Tyr by Phe revealed that PSGL-1 Tyr-51 plays a predominant role in mediating L-selectin binding and leukocyte rolling whereas Tyr-48 has a minor role, an observation that contrasts with the pattern seen for the interactions between PSGL-1 and P-selectin where Tyr-48 plays a key role. Molecular modeling analysis of L-selectin and P-selectin interactions with PSGL-1 further supported these observations. Additional experiments showed that core-2O-glycans attached to Thr-57 were also of critical importance in regulating the velocity and stability of leukocyte rolling. These observations pinpoint the structural characteristics of PSGL-1 that are required for optimal interactions with L-selectin and may be responsible for the specific kinetic and mechanical bond properties of the L-selectin-PSGL-1 adhesion receptor-counterreceptor pair.
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molecular basis of leukocyte rolling on psgl 1 predominant role of core 2 o glycans and of tyrosine sulfate residue 51
Journal of Biological Chemistry, 2003Co-Authors: Michael Pierre Bernimoulin, Xianlu Zeng, Claire Abbal, Sylvain Giraud, Manuel Martinez, Olivier Michielin, Marc Schapira, Olivier SpertiniAbstract:Interactions between the leukocyte adhesion receptor L-selectin and P-selectin glycoprotein ligand-1 play an important role in regulating the inflammatory response by mediating leukocyte tethering and rolling on adherent leukocytes. In this study, we have examined the effect of post-translational modifications of PSGL-1 including Tyr sulfation and presentation of sialylated and fucosylated O-glycans for L-selectin binding. The functional importance of these modifications was determined by analyzing soluble L-selectin binding and leukocyte rolling on CHO cells expressing various glycoforms of PSGL-1 or mutant PSGL-1 targeted at N-terminal Thr or Tyr residues. Simultaneous expression of core-2 beta1,6-N-acetylglucosaminyltransferase and fucosyltransferase VII was required for optimal L-selectin binding to PSGL-1. Substitution of Thr-57 by Ala but not of Thr-44, strongly decreased L-selectin binding and leukocyte rolling on PSGL-1. Substitution of Tyr by Phe revealed that PSGL-1 Tyr-51 plays a predominant role in mediating L-selectin binding and leukocyte rolling whereas Tyr-48 has a minor role, an observation that contrasts with the pattern seen for the interactions between PSGL-1 and P-selectin where Tyr-48 plays a key role. Molecular modeling analysis of L-selectin and P-selectin interactions with PSGL-1 further supported these observations. Additional experiments showed that core-2 O-glycans attached to Thr-57 were also of critical importance in regulating the velocity and stability of leukocyte rolling. These observations pinpoint the structural characteristics of PSGL-1 that are required for optimal interactions with L-selectin and may be responsible for the specific kinetic and mechanical bond properties of the L-selectin-PSGL-1 adhesion receptor-counterreceptor pair.