Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 1H nuclear magnetic resonance spectrum of alpha-tropomyosin contains a number of sharp peaks indicative of the presence of small regions of high flexibility in the molecule. Removal of 9 to 11 residues from the C-terminus by digestion with carboxypeptidase A causes a marked decline in the intensity of these peaks. The difference is consistent with at least the C-terminal four residues of the sequence (-Met-Thr-Ser-Ile) being highly mobile. The conformation of the C-terminus is thus radically different from the alpha-helical coiled-coil from which the bulk of the molecule is constructed.
J Mol Biol 1983 May 15
PMID:Nuclear magnetic resonance evidence for a flexible region at the C-terminus of alpha-tropomyosin. 685 45

The crystal structure of bovine carboxypeptidase A (Cox) has been refined at 1.54 A resolution using the restrained least-squares algorithm of Hendrickson & Konnert (1981). The crystallographic R factor (formula; see text) for structure factors calculated from the final model is 0.190. Bond lengths and bond angles in the carboxypeptidase A model have root-mean-square deviations from ideal values of 0.025 A and 3.6 degrees, respectively. Four examples of a reverse turn like structure (the "Asx" turn) requiring an aspartic acid or asparagine residue are observed in this structure. The Asx turn has the same number of atoms as a reverse turn, but only one peptide bond, and the hydrogen bond that closes the turn is between the Asx side-chain CO group and a main-chain NH group. The distributions of CO-N and NH-O hydrogen bond angles in the alpha-helices and beta-sheet structures of carboxypeptidase A are centered about 156 degrees. A total of 192 water molecules per molecule of enzyme are included in the final model. Unlike the hydrogen bonding geometry observed in the secondary structure of the enzyme, the CO-O(wat) hydrogen bond angle is distributed about 131 degrees, indicating the role of the lone pair electrons of the carbonyl oxygen in the hydrogen bond interaction. Twenty four solvent molecules are observed buried within the protein. Several of these waters are organized into hydrogen-bonded chains containing up to five waters. The average temperature factor for atoms in carboxypeptidase A is 8 A2, and varies from 5 A2 in the center of the protein, to over 30 A2 at the surface.
J Mol Biol 1983 Aug 05
PMID:Refined crystal structure of carboxypeptidase A at 1.54 A resolution. 688 46

4-Dimethylaminophenol, after i.v. injection, rapidly forms ferrihemoglobin and has been successfully used in the treatment of cyanide poisoning. The catalytic ferrihemoglobin formation is terminated by thioether formation of oxidized 4-dimethylaminophenol with reduced glutathione or cysteine 93 beta of hemoglobin. Hereby the physiological functions of human hemoglobin are markedly altered. After binding of two molecules of 4-dimethylaminophenol to tetrameric hemoglobin, the rate of autoxidation is increased about 6-fold. The oxygen affinity is 10 times higher than normal, the Hill coefficient is diminished nearly to unity, and the Bohr effect is reduced by about 50%. The physiologically important allosteric regulation of the oxygen affinity by 2,3-diphosphoglycerate is abolished, and the binding of 2,3-diphosphoglycerate to deoxyhemoglobin no longer functions. By molecular sieving, two alkylated hemoglobins were separated: a hemoglobin fraction with an unchanged low tetramer dimer dissociation, normal electronic spectra, and normal digestibility by carboxypeptidase A; and a second fraction with a high degree of dissociation, altered electronic spectra, and impaired digestibility. A tryptic peptide was isolated containing cysteine 93 beta and histidine 146 beta cross-linked by an arylic compound missing the dimethylamine label. The following reaction mechanism is concluded: Oxy-hemoglobin catalyzes the oxidation of 4-dimethylaminophenol, and the oxidation product, presumably N,N-dimethylquinonimine, is bound covalently to cysteine 93 beta by a thioether linkage. This adduct is unstable and autoxidizes further with the liberation of dimethylamine. The resulting quinoid thioether electrophilically attacks the COOH-terminal histidine of the beta-chain, thereby forming an intramolecular cross-link. By this latter reaction, hemoglobin lacks allosteric transition upon ligation and is obviously frozen in its quaternary R-state.
Mol Pharmacol 1983 Sep
PMID:Site and mechanism of covalent binding of 4-dimethylaminophenol to human hemoglobin, and its implications to the functional properties. 688 71

Semi-empirical calculation of conformational properties of covalent complexes of carboxypeptidase A with ester and peptide substrates are presented. There is a favourable form of transient tetrahedral and covalent acyl-enzyme intermediates in the active site of carboxypeptidase A. The ester and peptide substrates bind in the active site of carbopeptidase A in the same mode. The transition from one stage of the reaction to the other is followed by a small conformational change. The atom coordinates of the substrate component of these complexes are presented.
Mol Biol (Mosk)
PMID:[Theoretical conformational analysis of a substrate component of tetrahedral intermediates and of acyl-enzyme of carboxypeptidase A]. 724 37

Semi-empirical calculations of conformational properties of acetyl-L-tyrosine, glycyl-L-tyrosine, acetyl-L-alanyl-L-tyrosine and acetyl-L-alanyl-L-alanyl-tyrosine and their noncovalent complexes with carboxypeptidase A (CPA) are presented. Each of these molecules binds in the active site of CPA by only one binding mode. The substrates are practically free of intramolecular tension. It is shown that the binding of an aromatic side chain of a C-terminal residue of substrate provides productive orientation of the susceptible peptide bond. The sterochemical aspects of the interactions of Tyr-248 and Glu-270 residues with the substrates are considered.
Mol Biol (Mosk)
PMID:[Theoretical conformational analysis of noinvalent carboxypeptidase A complexes with inhibitors and substrates]. 742 20

We have carried out studies to ascertain whether the histamine-containing, IgE-bearing cells found in the bronchoalveolar lavage (BAL) fluid obtained during the late-phase response following subsegmental antigen challenge of human airways are predominantly basophils or mast cells. Four lines of evidence suggest that most are basophils: (1) The cells fulfill morphologic criteria for light microscopy. (2) Cell surface markers determined by immunofluorescence and flow cytometry revealed that the IgE-bearing cells express the leukocyte antigens Fc gamma RII and the beta 2 integrins, LFA-1 and Mac-1, but do not express the mast cell-associated c-kit receptor for stem cell factor. (3) The late-phase histamine-containing cells in late-phase BAL fluids have the functional characteristics of basophils in their secretory responses to anti-IgE, the f-met peptide, and phorbol ester TPA. (4) The cells have a functional histamine type 2 receptor, a characteristic of basophils, not mast cells. We conclude that basophils infiltrate the lower airways hours after antigen exposure. These cells may be responsible for the mediator release observed at that time.
Am J Respir Cell Mol Biol 1994 Apr
PMID:Identification of IgE-bearing cells in the late-phase response to antigen in the lung as basophils. 751 Sep 84

We have analyzed the biophysical and pharmacological properties of five cloned K+ (Kv) channels (Kv1.1, Kv1.2, Kv1.3, Kv1.5, and Kv3.1) stably expressed in mammalian cell lines. Kv1.1 is biophysically similar to a K+ channel in C6 glioma cells and astrocytes, Kv1.3 and Kv3.1 have electrophysiological properties identical to those of the types n and l K+ channels in T cells, respectively, and Kv1.5 closely resembles a rapidly activating delayed rectifier in the heart. Each of these native channels may be formed from the homomultimeric association of the corresponding Kv subunits, and pharmacological compounds that selectively modulate them may be useful for the treatment of neurological, immune, and cardiac disorders. The cell lines described in this report could be used to identify such drugs and we have therefore embarked on a pharmacological characterization of the five cloned channels. The compounds tested in this study include 4-aminopyridine, capsaicin, charybdotoxin, cromakalim, dendrotoxin, diltiazem, D-sotalol, flecainide, kaliotoxin, mast cell degranulating peptide, nifedipine, noxiustoxin, resiniferatoxin, and tetraethylammonium.
Mol Pharmacol 1994 Jun
PMID:Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. 751 98

Serine proteinases participate in many inflammatory events in the airway. We therefore screened perfusates of isolated rat tracheas for tryptic, elastolytic, and chymotryptic serine proteinases. Only chymotryptic activity, indicated by hydrolysis of the synthetic substrate N-succinylalanylalanylprolylphenylalanyl p-nitroaniline (AAPF), was consistently detected in these perfusates. Basal levels of chymotryptic activity were not increased significantly by electrical field stimulation (EFS) (mean change +/- SEM: -0.05 +/- 0.05 m o.d. units, n = 4) or by 10(-7) M substance P (SP) (+0.04 +/- 0.02 m o.d. units, n = 14). However, the mean change after the stimuli were jointly administered (0.17 +/- 0.06 m o.d. units, n = 12) was significantly greater than control or after EFS (P = 0.01, one-way ANOVA). The SP + EFS-induced chymotryptic activity was inhibited by PMSF, soybean trypsin inhibitor, and chymostatin and was associated with an increase in histamine concentration and immunoreactivity to rat mast cell proteases (RMCP), indicating that the activity is due to mast cell degranulation. However, the activity was not significantly decreased by pretreating rats with systemic compound 48/80. SP + EFS-induced chymotryptic activity peaked rapidly and was associated with modest histamine release and an immediate peak in immunoreactivity to RMCP II, a marker of mucosal mast cells. Immunoreactivity to RMCP I, a marker of connective tissue mast cells, also increased after SP + EFS, but this immunoreactivity was either delayed or more sustained and did not coincide with the peak of chymotryptic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Sep
PMID:Chymotryptic activity in perfusates of isolated rat trachea: correlation with mucosal and connective tissue mast cell secretion. 752 16

Activation of protein tyrosine kinases is one of the initial events following aggregation of the high-affinity receptor for immunoglobulin E (Fc epsilon RI) on RBL-2H3 cells, a model mast cell line. The protein tyrosine kinase p72syk (Syk), which contains two Src homology 2 (SH2) domains, is activated and associates with phosphorylated Fc epsilon RI subunits after receptor aggregation. In this report, we used Syk SH2 domains, expressed in tandem or individually, as fusion proteins to identify Syk-binding proteins in RBL-2H3 lysates. We show that the tandem Syk SH2 domains selectively associate with tyrosine-phosphorylated forms of the gamma and beta subunits of Fc epsilon RI. The isolated carboxy-proximal SH2 domain exhibited a significantly higher affinity for the Fc epsilon RI subunits than did the amino-proximal domain. When in tandem, the Syk SH2 domains showed enhanced binding to phosphorylated gamma and beta subunits. The conserved tyrosine-based activation motifs contained in the cytoplasmic domains of the gamma and beta subunits, characterized by two YXXL/I sequences in tandem, represent potential high-affinity binding sites for the dual SH2 domains of Syk. Peptide competition studies indicated that Syk exhibits a higher affinity for the phosphorylated tyrosine activation motif of the gamma subunit than for that of the beta subunit. In addition, we show that Syk is the major protein in RBL-2H3 cells that is affinity isolated with phosphorylated peptides corresponding to the phosphorylated gamma subunit motif. These data suggest that Syk associates with the gamma subunit of the high-affinity receptor for immunoglobulin E through an interaction between the tandem SH2 domains of SH2 domains of Syk and the phosphorylated tyrosine activation motif of the gamma subunit and that Syk may be the major signaling protein that binds to Fc epsilon RI tyrosine activation motif of the gamma subunit and that Syk may be the major signaling protein that binds to Dc epsilon tyrosine activation motifs in RBL-2H3 cells.
Mol Cell Biol 1995 Jan
PMID:Interaction of p72syk with the gamma and beta subunits of the high-affinity receptor for immunoglobulin E, Fc epsilon RI. 752 27

In mast cells, antigen-mediated aggregation of the high-affinity receptor for immunoglobulin E, Fc epsilon RI, stimulates tyrosine phosphorylation and activation of multiple signaling pathways leading to the release of several classes of mediators of the allergic response. Early events induced upon cross-linking of Fc epsilon RI include tyrosine phosphorylation of Fc epsilon RI subunits and activation of the tyrosine kinase p72syk (Syk), which binds to tyrosine-phosphorylated Fc epsilon RI. Clustering of Syk, as a result of its interaction with aggregated Fc epsilon RI, may play a role in activating one or more of the signaling pathways leading to mediator release. To test this possibility, Syk was introduced into a model mast cell line (rat basophilic leukemia cells) as part of a chimeric transmembrane protein containing the extracellular and transmembrane domains of CD16 and CD7, respectively. Clustering of the Syk chimera, using antibodies against CD16, was found to be sufficient to stimulate early and late events normally induced by clustering of Fc epsilon RI. Specifically, aggregation of Syk induced degranulation, leukotriene synthesis, and expression of cytokine genes. Induction of mediator release was dependent on the kinase activity of Syk. Consistent with this finding, clustering of Syk also induced the tyrosine phosphorylation of a profile of proteins, including phospholipase C-gamma 1 and mitogen-activated protein kinase, similar to that induced upon clustering of Fc epsilon RI. These results strongly suggest that Syk is an early and critical mediator of multiple signaling pathways that emanate from the Fc epsilon RI receptor and give rise to the allergic response.
Mol Cell Biol 1995 Mar
PMID:Clustering of Syk is sufficient to induce tyrosine phosphorylation and release of allergic mediators from rat basophilic leukemia cells. 753 80


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