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P-Selectin (CD62, PADGEM, GMP140) is a membrane glycoprotein which is rapidly
mobilized to the surface of activated platelets and endothelial cells where it
mediates leukocyte-platelet and leukocyte-vascular endothelial cell adhesion,
respectively. P-Selectin is a member of a family of adhesion molecules which
includes the endothelial cell adhesion molecule E-selectin and the leukocyte
adhesion molecule L-selectin. Selectins mediate cell-cell binding resulting from
the interaction between the amino terminal lectin domains of the selectins and
their respective carbohydrate ligands. Here we report on a three-dimensional
model of the lectin domain of P-selectin which was derived on the basis of its
structural homology to the rat mannose binding protein (MBP) whose crystal
structure has recently been reported. On the basis of the model, a number of
point mutants were prepared to identify the P-selectin binding site. The
residues found to be important for binding are located in a shallow groove on
the surface of the molecule composed of residues from the beta-2, -3, and -5
strands of the P-selectin lectin domain. A number of residues within this
groove, which are conserved among all selectins, were found to be critical for
P-selectin binding. They include Lys113, Tyr48, and Tyr94. The single
substitutions Lys113Ala, Tyr48Ala, Tyr48Phe, Tyr94Ala, and Tyr94Phe abolished
P-selectin binding to myeloid cells.
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