Effects of chemical modification on the binding activities of P-selectin mutants

Biochemistry
D HollenbaughP D Senter

Abstract

P-Selectin (GMP140, CD62P, PADGEM), a 140-kDa glycoprotein found on activated platelets and endothelial cells, is involved in one of the early events in the inflammatory response due to its role in initiating the recruitment of circulating leukocytes. From a three-dimensional model of P-selectin and site-specific mutagenesis studies, a number of residues were previously identified as critical for the binding of P-selectin to HL-60 cells, a human myeloid cell line. Included among them were lysines 111 and 113 (K111 and K113). In this study, the roles of K111 and K113 were further characterized by the generation and specific chemical modification of two cysteine mutants, K111C and K113C, of a P-selectin-immunoglobulin fusion protein (P-selectin-Rg). Both K111C and K113C displayed significantly reduced binding activity compared to the wild-type P-selectin from which they were derived, further illustrating the importance of these particular lysines for ligand binding. Reaction of K111C with aziridine or nipsylcysteamine resulted in the formation of K111C-AZ and K111C-CY, both of which displayed significant increases in HL-60 binding activity. No such increase took place upon reaction of K111C with N-ethylmaleimide, indicating that ...Continue Reading

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Feb 1, 1996·Trends in Biotechnology·S M Chamow, A Ashkenazi
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