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Glanzmann thrombasthenia due to a two amino acid deletion in the fourth
calcium-binding domain of alpha IIb: demonstration of the importance of
calcium-binding domains in the conformation of alpha IIb beta 3
RB Basani, G Vilaire, SJ Shattil, MA Kolodziej, JS Bennett and M Poncz
Department of Pediatrics, University of Pennsylvania School of Medicine,
Philadelphia, USA.
The integrin alpha IIb beta 3, a calcium-dependent heterodimer, plays a
critical role in platelet aggregation. The alpha IIb subunit of the
heterodimer contains four highly conserved putative calcium-binding domains
in its extracellular portion. During studies of the molecular basis of
Glanzmann thrombasthenia in a child of mixed Caucasian background whose
platelets expressed little alpha IIb beta 3 on their surface, we found the
patient heterozygous for a two amino acid deletion in the fourth alpha IIb
calcium-binding domain. When this alpha IIb mutant was expressed in COS-1
cells, we found that the deletion did not interfere with the assembly of
alpha IIb beta 3 heterodimers, but altered their conformation such that
they were neither recognized by the heterodimer-specific antibody A2A9 nor
able to undergo further intracellular processing or transport to the cell
surface. These results suggest that the calcium-binding domains in alpha
IIb play an important role maintaining the overall conformation of alpha
IIb beta 3. To confirm this suggestion, we deleted each of the four 12
amino acid calcium-binding domains in alpha IIb by in vitro mutagenesis and
expressed the mutants along with beta 3 in COS-1 cells. Each construct
formed a heterodimer with beta 3, but none of the heterodimers interacted
with A2A9 or underwent further intracellular processing. These data
indicate that the calcium-binding domains in alpha IIb are not involved in
alpha IIb beta 3 heterodimer formation, but their presence is required for
the intracellular transport of alpha IIb beta 3 to the cell surface.
Volume 88,
Issue 1,
pp. 167-173,
07/01/1996
Copyright © 1996 by The American Society of Hematology
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