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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 302-309
The Carboxy-Terminal Cell-Binding Domain of Thrombospondin Is
Essential for Sickle Red Blood Cell Adhesion
Cheryl A. Hillery,
J. Paul Scott, and
Ming C. Du
From the Department of Pediatrics, Medical College of Wisconsin,
Milwaukee; and the Blood Research Institute, The Blood Center of
Southeastern Wisconsin, Milwaukee.
Sickle red blood cells (SS-RBCs) have enhanced adhesion to the
plasma and subendothelial matrix protein thrombospondin-1 (TSP) under
conditions of flow in vitro. TSP has at least four domains that mediate
cell adhesion. The goal of this study was to map the site(s) on TSP
that binds SS-RBCs. Purified TSP proteolytic fragments containing
either the N-terminal heparin-binding domain, or the type 1, 2, or 3 repeats, failed to sustain SS-RBC adhesion (<10% adhesion). However,
a 140-kD thermolysin TSP fragment, containing the
carboxy-terminal cell-binding domain in addition to the type 1, 2, and
3 repeats fully supported the adhesion of SS-RBCs (126% ± 25%
adhesion). Two cell-binding domain adhesive peptides, 4N1K (KRFYVVMWKK)
and 7N3 (FIRVVMYEGKK), failed to either inhibit or support SS-RBC
adhesion to TSP. In addition, monoclonal antibody C6.7, which blocks
platelet and melanoma cell adhesion to the cell-binding domain, did not
inhibit SS-RBC adhesion to TSP. These data suggest that a novel
adhesive site within the cell binding domain of TSP promotes the
adhesion of sickle RBCs to TSP. Furthermore, soluble TSP did not bind
SS-RBCs as detected by flow cytometry, nor inhibit SS-RBC adhesion to
immobilized TSP under conditions of flow, indicating that the adhesive
site on TSP that recognizes SS-RBCs is exposed only after TSP binds to
a matrix. We conclude that the intact carboxy-terminal cell-binding
domain of TSP is essential for the adhesion of sickle RBCs under flow
conditions. This study also provides evidence for a unique adhesive
site within the cell-binding domain that is exposed after TSP binds to
a matrix.
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