Blood Cells Mol Dis 1995 Jan 01;212:131-41. doi: 10.1006/bcmd.1995.0015.

The P1A alloantigen system is a sensitive indicator of the structural integrity of the amino-terminal domain of the human integrin beta 3 subunit.

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Within the native integrin alpha pi b beta 3, the conformation of the amino-terminal domain of the beta 3 subunit has a significant influence on the availability of the Leu33/Pro33 polymorphism that defines the A1 and A2 alleles, respectively, of the P1A alloantigen system. The majority of anti-P1A1 IgG antibodies, affinity-purified by adsorption to either (A1/A1)-platelets or purified alpha pi b(A1) beta 3, fail to bind to the Leu33 polymorphic loop within Cys26-Cys38 in native beta 3 unless this sequence is maintained in a proper orientation by two noncontiguous human beta 3 sequences. By comparing IgG binding to recombinant beta 3 molecules composed of segments of human, Xenopus and avian sequences expressed by Spodoptera frugiperda cell lines, we have found that neither region alone is sufficient for full expression of the epitope. One sequence, that most proximal to Leu33/Pro33, lies within beta 3[54-133], and a second distal sequence is located within beta 3[435-490]. Proximity of the distal sequence to the Cys26-Cys38 loop in native beta 3 is confirmed by the fact that both anti-P1A1 IgG and the murine monoclonal antibody SZ21, specific for beta 3[28-35], completely inhibit the binding of rabbit polyclonal IgG specific for the sequence beta 3[479-485]. Anti-P1A1 IgG antibodies from all of the 7 donors selectively bind to the epitope within the native conformation of beta 3. However, in one of the seven donors, roughly 60% of the anti-P1A1IgG binds exclusively to denatured (A1) beta 3, and not to either denatured (A2) beta 3 or nondenatured (native) (A1) beta 3. This IgG subpopulation cannot be purified by adsorption to intact (A1/A1)-platelets or to native alpha pi b(A1) beta 3 integrin. The physiologic relevance of this exceptional type of anti-P1A1 antibody is debatable, but the presence of IgG with this specificity only in an immunized subject suggests that the epitope may well be presented on a "denatured" form of beta 3 in vivo. Regardless, our results indicate that the amino-terminal domain of the native beta 3 molecule associates with noncontiguous beta 3 sequences, and the epitope recognized by a majority of anti-P1A1 antibodies is a sensitive indicator of correct tertiary structure within this region of beta 3.

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