Biomedical subjects

D Dörmann

Publications and source records attributed to D Dörmann.

4 recordsLinked to original sources

PubMed2001

Echicetin, a GPIb-binding snake C-type lectin from Echis carinatus, also contains a binding site for IgMkappa responsible for platelet agglutination in plasma and inducing signal transduction.

Echicetin, a heterodimeric snake C-type lectin from Echis carinatus, is known to bind specifically to platelet glycoprotein (GP)Ib. We now show that, in addition, it agglutinates platelets in plasma and induces platelet signal transduction. The agglutination is caused by binding to a specific protein in plasma. The protein was isolated from plasma and shown to cause platelet agglutination when added to washed platelets in the presence of echicetin. It was identified as immunoglobulin Mkappa (IgMkappa) by peptide sequencing and dot blotting with specific heavy and light chain anti-immunoglobulin reagents. Platelet agglutination by clustering echicetin with IgMkappa induced P-selectin expression and activation of GPIIb/IIIa as well as tyrosine phosphorylation of several signal transduction molecules, including p53/56(LYN), p64, p72(SYK), p70 to p90, and p120. However, neither ethylenediaminetetraacetic acid nor specific inhibition of GPIIb/IIIa affected platelet agglutination or activation by echicetin. Platelet agglutination and induction of signal transduction could also be produced by cross-linking biotinylated echicetin with avidin. These data indicate that clustering of GPIb alone is sufficient to activate platelets. In vivo, echicetin probably activates platelets rather than inhibits platelet activation, as previously proposed, accounting for the observed induction of thrombocytopenia.

Acetates↗

PubMed2001

Alboaggregin A activates platelets by a mechanism involving glycoprotein VI as well as glycoprotein Ib.

The snake venom C-type lectin alboaggregin A (or 50-kd alboaggregin) from Trimeresurus albolabris was previously shown to be a platelet glycoprotein (GP) Ib agonist. However, investigations of the signal transduction induced in platelets showed patterns of tyrosine phosphorylation that were different from those of other GPIb agonists and suggested the presence of an additional receptor. In this study, the binding of biotinylated alboaggregin A to platelet lysates, as well as affinity chromatography evaluations of platelet lysates on an alboaggregin A-coated column, indicated that this other receptor is GPVI. Additional experiments with reagents that inhibit either GPIb or GPVI specifically supported this finding. These experiments also showed that both GPIb and GPVI have a role in the combined signaling and that the overall direction this takes can be influenced by inhibitors of one or the other receptor pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2000

The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity.

The role of the platelet glycoprotein (GP) Ib-V-IX receptor in thrombin activation of platelets has remained controversial although good evidence suggests that blocking this receptor affects platelet responses to this agonist. The mechanism of expression of procoagulant activity in response to platelet agonists is also still obscure. Here, the binding site for thrombin on GPIb is shown to have a key role in the exposure of negatively charged phospholipids on the platelet surface and thrombin generation, in response to thrombin, which also requires protease-activated receptor-1, GPIIb-IIIa, and platelet-platelet contact. Von Willebrand factor binding to GPIb is not essential to initiate development of platelet procoagulant activity. Inhibition of fibrinogen binding to GPIIb-IIIa also failed to block platelet procoagulant activity. Both heparin and low molecular weight heparin block thrombin-induced platelet procoagulant activity, which may account for part of their clinical efficacy. This study demonstrates a new, critical role for platelet GPIb in hemostasis, showing that platelet activation and coagulation are tightly interwoven, which may have implications for alternative therapies for thrombotic diseases.

Adult↗

PubMedDate not supplied

Multifunctional snake C-type lectins affecting platelets.

Snake venoms contain a wide range of components, many of which affect haemostasis by activation or inhibition of platelets or coagulation factors. They can be classified into groups based on structure and mode of action. One group is the snake C-type lectins, so called because of the typical folding which closely resembles that found in classical C-type lectins, such as selectins and mannose-binding proteins. Unlike the classic C-type lectins, those from snakes are generally heterodimeric with two subunits, alpha and beta. Some are multimeric heterodimers. The subunits have homologous sequences and are generally linked by a disulphide bond as well as by swapping loops. One of the first C-type lectins with a defined function was echicetin which was demonstrated to bind to platelet GPIb and block several functions of this receptor. Since then, many proteins with similar structure have been reported to act on platelet receptors or coagulation factors and several have been crystallized. These proteins were thought to be specific for a single platelet receptor or coagulation factor, i.e. they had only one receptor per heterodimer. Recent studies show that most of these C-type lectins have binding sites for more than one ligand and have complex mechanisms of action.

Animals↗