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Friday, 30 January 2004
Towards a Better Understanding of the Platelet Activation Mechanismsummary written by Irimpan Mathews, SSRL, and Heather Rock Woods, SLAC Communication OfficeKottayil I. Varughese (kiv@scripps.edu), Zaverio M. Ruggeri (ruggeri@scripps.edu) and Reha Celikel (reha@scripps.edu)
When a blood vessel is cut, the body activates a repair mechanism that
eventually seals the cut and prevents further blood loss. This life saving
process becomes life threatening when clots form inside a functional blood
vessel. Arrest of bleeding works through platelet adhesion and
thrombin-induced fibrin formation at the site of injury. In order for the
platelets to stick to the injured tissues and to each other, they need to be
activated. Thrombin is an essential protease (a type of enzyme) that activates
platelets and forms blood clots in response to vascular injury.
Researchers at The Scripps Research Institute have successfully crystallized
a-thrombin with a portion of the platelet receptor
GpIba, and determined the structure to a resolution
of 2.3 angstroms. Their structural analysis shows that the thrombin uses two
of its active regions, exosite I and exosite II, to bind to GpIba. There were conflicting reports in the literature
favoring the binding of exosite I or exosite II to GpIba. The dual binding interaction observed in the
current structure has the potential to stimulate receptor clustering on the
platelet surface, thus promoting platelet signaling and activation. In
addition to this, the dual mode interaction with GpIba may be an important factor in not exceeding the proper
amount of clotting after
a-thrombin generation at sites of vascular injury.
When GpIba is bound to
exosite I, it limits the pro-thrombotic function of a-thrombin by reducing its
fibrinogen clotting activity.
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