Disruption of the β3 663-687 disulfide bridge confers constitutive activity to β3 integrins

The platelet fibrinogen receptor, integrin alpha(IIb)beta(3), is a noncovalent heterodimer of glycoproteins IIb and IIIa. This work was aimed at elucidating the role played by the carboxy-terminal extracellular, transmembrane, and cytoplasmic regions of the glycoprotein beta(3) in the formation of functional complexes with alpha subunits. Progressive carboxy-terminal deletions of beta(3) revealed that surface exposure of alpha(IIb)beta(3) or alpha(V)beta(3) could not occur in the absence of the transmembrane domain of beta(3). In contrast, internal deletions 616 to 690 of the carboxy-terminal regions of the beta(3) ectodomain led to surface exposure of constitutive active receptors in CHO cells, as indicated by the enhanced rate of cell adhesion to immobilized ligands and spontaneous binding to soluble fibrinogen or activation-dependent antibody PAC-1. The functional analysis of cysteine mutations within the 616 to 690 region of beta(3) or chimeric beta(3)-beta(7) subunits revealed that disruption of the C663-C687 disulfide bridge endows constitutive activity to the alpha(IIb)beta(3) receptor. it is concluded that the carboxy-terminal tail of the beta(3) ectodomain, so-called beta tail domain (betaTD), is not essential for cell surface expression of beta(3) receptors. However, a basal, nonactivated, low ligand-affinity state of the beta(3) integrins demands a normal conformation of this domain. (C) 2003 by The American Society of Hematology.