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Blood, 22 January 2009, Vol. 113, No. 4, pp. 902-910.
Prepublished online as a Blood First Edition Paper on November 5, 2008; DOI 10.1182/blood-2008-09-177337.
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PLATELETS AND THROMBOPOIESIS
Species differences in small molecule binding to  IIbβ3 are the result of sequence differences in 2 loops of the IIb β propeller
Ramesh B. Basani1,
Hua Zhu2,
Michael A. Thornton1,3,
Cinque S. Soto4,
William F. DeGrado4,
M. Anna Kowalska1,
Joel S. Bennett2, and
Mortimer Poncz1
1 Division of Hematology, Children's Hospital of Philadelphia, PA;
2 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia;
3 Department of Biology, Florida A&M University, Tallahassee; and
4 Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia
Compared with human platelets, rodent platelets are less responsive to peptides and peptidomimetics containing an arginine-glycine-aspartic acid (RGD) motif. Using chimeric human-rat  IIbβ3 molecules, we found that this difference in Arg-Gly-Asp-Ser (RGDS) sensitivity was the result of amino acid substitutions at residues 157, 159, and 162 in the W3:4-1 loop and an Asp-His replacement at residue 232 in the W4:4-1 loop of the IIb β propeller. Introducing the entire rat W3:4-1 and W4:4-1 loops into human IIbβ3 also decreased the inhibitory effect of the disintegrins, echistatin and eristostatin, and the IIbβ3 antagonists, tirofiban and eptifibatide, on fibrinogen binding, whereas the specific point mutations did not. This suggests that RGDS interacts with IIb in a different manner than with these small molecules. None of these species-based substitutions affected the ability of IIbβ3 to interact with RGD-containing macromolecules. Thus, human von Willebrand factor contains an RGD motif and binds equally well to adenosine diphosphate-stimulated human and rodent platelets, implying that other motifs are responsible for maintaining ligand binding affinity. Many venoms contain RGD-based toxins. Our data suggest that these species amino acids differences in the IIb β-propeller represent an evolutionary response by rodents to maintain hemostasis while concurrently protecting against RGD-containing toxins.
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R. Blue, M. A. Kowalska, J. Hirsch, M. Murcia, C. A. Janczak, A. Harrington, M. Jirouskova, J. Li, R. Fuentes, M. A. Thornton, et al.
Structural and therapeutic insights from the species specificity and in vivo antithrombotic activity of a novel {alpha}IIb-specific {alpha}IIb{beta}3 antagonist
Blood,
July 2, 2009;
114(1):
195 - 201.
[Abstract]
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