Summary
The glycoprotein (GP) IIb/IIIa, a Ca2+-dependent heterodimer, is the major integrin on the platelet plasma membrane. On
resting platelets GPIIb/IIIa is maintained in an inactive conformation and serves
as a low affinity adhesion receptor for surface-coated fibrinogen, whereas upon platelet
activation signals within the cytoplasma alter the receptor function of GPIIb/IIIa
(inside-out signalling), which undergoes a measurable conformational change within
its exoplasmic domains, and becomes a competent receptor for soluble fibrinogen and
some other RGD sequence-containing plasma adhesive proteins. Upon ligand binding,
further structural alterations trigger the association of receptor-occupied GPIIb/IIIa
complexes with themselves within the plane of the membrane. The simultaneous binding
of dimeric fibrinogen molecules to GPIIb/IIIa clusters on adjacent platelets leads
to platelet aggregation, which promotes attachment of fibrinogen-GPIIb/IIIa clusters
to the cytoskeleton (outside-in signalling). This, in turn, provides the necessary
physical link for clot retraction to occur, and generates a cascade of intracellular
biochemical reactions which result in the formation of a multiprotein signalling complex
at the cytoplasmic domains of GPIIb/IIIa. Glycoprotein IMIIa, also called αIIbβ3 in the integrin nomenclature, plays thus a primary role in both platelet adhesion
and thrombus formation at the site of vascular injury. In addition, the human glycoprotein
Ilb/IIIa complex is the most thoroughly studied integrin receptor, its molecular biology
and major features of its primary structure having been elucidated mainly during the
last six years. Furthermore, localization of functionally relevant monoclonal antibody
epitopes, determination of the cross-linking sites of inhibitory peptide ligands,
proteolytic dissection of the isolated integrin, and analysis of natural and artificial
GPIIb/IIIa mutants have recently provided a wealth of information regarding structure-function
relationships of human GPIIb/IIIa. The aim of this review is to summarize these many
structural and functional data in the perspective of an emerging model. Although most
of the interpretations based on structural elements of this initial biochemical model
require independent confirmation, they may help us to understand the structure-function
relationship of this major platelet receptor, and of other members of the integrin
superfamily, as well as to perform further investigations in order to test current
hypotheses.
