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The impact of three-dimensional structure on the expression of PlA
alloantigens on human integrin beta 3
S Honda, Y Honda, B Bauer, C Ruan and TJ Kunicki
Department of Molecular and Experimental Medicine, Scripps Research
Institute, La Jolla, CA 92017, USA.
We have compared the binding of affinity-purified anti-PlA1 IgG from seven
nonrelated donors with chimeric integrin subunit beta 3 molecules expressed
in the baculovirus-Spodoptera frugiperda insect cell system. Beta 3
chimeras were engineered to include segments of antigenic human beta 3
sequences spliced to intervening segments of nonantigenic Xenopus beta 3
sequence. Our results clearly show that antibodies from all seven donors
will bind to nondenatured molecules containing the antigenic human beta 3
Cys26-Cys38 loop only when it is presented in a correct orientation that
must be maintained by noncontiguous human sequences. Key downstream
sequences are located within the region beta 3(288-490), flanking either
side of the putative long-range disulfide at Cys435. Although our results
confirm unambiguously that the Leu/Pro polymorphism at position 33 in human
beta 3 is necessary for the expression of PlA epitopes, they also indicate
that this polymorphic sequence alone is not sufficient. The requirement for
additional human beta 3 sequence transcends the need to maintain a correct
orientation within the Cys26-Cys38 loop itself, because the murine
monoclonal antibody SZ21, which recognizes the sequence beta 3(28-35)
contained within the Cys26-Cys38 loop, binds to all chimeras containing
this loop, even if the same chimeras are not recognized by anti-PlA1. Our
results indicate that additional noncontiguous residues encompassed by the
sequence 288-490 either directly contribute to the composition of the PlA1
epitope or, more likely, maintain the Cys26-Cys38 loop in a proper
orientation with respect to the remainder of the beta 3 molecule and
thereby maintain proper antigenic presentation of the sequences in that
loop.
Volume 86,
Issue 1,
pp. 234-242,
07/01/1995
Copyright © 1995 by The American Society of Hematology
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