• Overview
• Leukocyte Transmigration
• JAMs
• Selectins
• Integrins
• VLA-4/VCAM-1
• LFA-1/ICAM-1

Adhesion Molecules of Leukocyte Trafficking : Selectins

Selectins

The selectins are comprised of three closely related transmembrane proteins: P-selectin, L-selectin, and E-selectin (Bevilacqua, 1993). P-selectin is the largest (140kDa) and is expressed on nearly all circulating leukocytes and activated endothelial cells ( Bruehl et al., 1997). It contains an N-terminal extracellular domain with structural homology to Ca 2+ dependent lectins, an epidermal growth factor (EGF)-like domain, a series of nine short consensus repeats (SCR) domains, a transmembrane domain and a cytoplasmic tail. The primary ligand for P-selectin is PSGL-1, a 240 kDa mucin-like glycoprotein constitutively expressed as a disulfide-linked homodimer on the microvilli of all leukocytes ( McEver and Cummings, 1997). Important P-selectin binding determinants expressed by PSGL-1 include several serine/threonine repeats and O-glycosylated domains.

Structural Basis for the Interaction between P-selectin and PSGL-1

The N-terminal lectin domain of P-selectin is responsible for PSGL-1 binding in a Ca 2+-dependent manner. P-selectin binds with relatively high affinity (K d~300 nM) to PSGL-1 by reacting with the anionic N-terminus of PSGL-1 that is decorated with an O-linked sialyl Lewis X (sLeX) glycan attached to Thr-57 and one or more tyrosine sulfate residues (Mehta et al., 1998)(Epperson et al., 2000)(Maly et al., 1996). The molecular contacts between P-selectin and PSGL-1 were identified by analysis of the crystal structure of P-selectin complexed with an N-terminal peptide of PSGL-1 (Somers et al., 2000). These studies revealed the direct involvement of the Fuc, Gal and NeuNAc residues of the sLeX tetrasaccharide (NeuNAc2,3Gal1,4[Fuc1,3]GlcNAc) in selectin binding. The importance of the Fuc residue and sialic acid groups is underscored by the fact that cells deficient in the fucosyltransferase VII (FucT-VII), an enzyme that attached Fuc to core- 2 glycans, and cells treated with neuraminidase to remove the sialic acid groups failed to bind selectin expressing cells. In both P-selectin/sLeX and E-selectin/sLeX structures, the 3- and 4- hydroxyl groups of the Fuc residue of sLeX are ligated to the coordinated calcium cation of the selectins. In addition, the selectin/sLeX complex is stabilized by hydrogen bonds between the side chains of Tyr-94 and Glu-92 and 4-hydroxyl and 5-hydroxyl groups of the Gal residue, respectively. The interactions between the sialic acid residue and P- and E-selectins are stabilized by hydrogen bonds between Tyr-48 of the selectin molecule and the carboxyl group of NeuNAc, and between the 4-hydroxy group and Ser-99 of the selectins. These results are consistent with functional studies that have identified these determinants in stabilizing the velocity of P-selectin-mediated rolling (Rodgers et al., 2001).