On the structure and function of platelet integrin alpha IIb beta 3, the fibrinogen receptor

Abstract

Platelet membrane glycoprotein (GP) IIb/IIIa (alpha IIb beta 3), a Ca(2+)-dependent heterodimer, serves as an inducible receptor for fibrinogen and other adhesive plasma proteins, and is the most thoroughly studied integrin receptor. Intensive research during the past several years has elucidated the major features of its biosynthetic pathway, covalent structure, domain organization, and topography, and we are beginning to get an insight into the cellular mechanisms controlling integrin function. The emerging picture indicates that platelet-specific elements initiate at the cytoplasmic domains of GPIIb/IIIa a signal that leads to conformational changes within the integrin's extracellular domains and expression of the fibrinogen receptor. The simultaneous occupancy on adjacent platelets of receptors with dimeric fibrinogen molecules leads to platelet aggregation. Further structural alterations promote clustering of occupied GPIIb/IIIa complexes and their attachment to the remodelling cytoskeletal network. This interaction provides the physical link for clot retraction to occur and appears to regulate the compartmentalization, and local activation, of a multienzymatic complex which translates the ligand-binding information into time-dependent irreversibility of the fibrinogen-GPIIb/IIIa interaction. Platelet GPIIb/IIIa plays, thus, a central role in thrombus formation both in health and disease: abnormalities in the platelet adhesive mechanisms responsible for the formation of the hemostatic plug, lead to major pathophysiologic disorders, ranging from severe bleeding to thrombosis. It is, therefore, not surprising that GPIIb/IIIa has been the subject of intensive research during the last decades, since a detailed knowledge of the molecular biology and the mechanism underlying the platelet activation and aggregation processes may aid in the rational design of both an effective gene replacement therapy, and of potent and specific anti-thrombotic drugs. The aim of this minireview is to summarize many functional and structural data from different laboratories in the perspective of an emerging model that may help us to understand structure-function relationships of GPIIb/IIIa and of other members of the integrin family.