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P-selectin glycoprotein ligand-1 plays a crucial role in the selective recruitment of leukocytes into the atherosclerotic arterial wall.

ABSTRACT: Leukocyte recruitment to the arterial vessel wall is the first step in the development of atherosclerotic lesions. Leukocyte homing in this event proceeds through a well-defined adhesion cascade, which includes tethering, rolling, adhesion, and transmigration. Selectins, including the P-, E-, and L-selectins, and their ligands mediate the initial tethering and rolling. Interactions between selectins and their ligands serve as a braking system to decelerate fast-flowing leukocytes from the central blood stream and enable them to adhere to and transmigrate underneath the activated endothelium. The best characterized ligand for selectins is P-selectin glycoprotein ligand-1, an extended homodimeric mucin on leukocytes that binds to all three selectins. Recent studies show that differential expression or glycosylation of P-selectin glycoprotein ligand-1 in different leukocytes mediates selective recruitment of different subsets of monocytes or lymphocytes to atherosclerotic arteries.

SUBMITTER: Huo Y

PROVIDER: S-EPMC2762112 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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P-selectin glycoprotein ligand-1 plays a crucial role in the selective recruitment of leukocytes into the atherosclerotic arterial wall.

Huo Yuqing Y Xia Lijun L

Trends in cardiovascular medicine 20090501 4

Leukocyte recruitment to the arterial vessel wall is the first step in the development of atherosclerotic lesions. Leukocyte homing in this event proceeds through a well-defined adhesion cascade, which includes tethering, rolling, adhesion, and transmigration. Selectins, including the P-, E-, and L-selectins, and their ligands mediate the initial tethering and rolling. Interactions between selectins and their ligands serve as a braking system to decelerate fast-flowing leukocytes from the centra ...[more]

PMID: 19818951

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Project description:BACKGROUND: P-selectin glycoprotein ligand-1 (PSGL-1) plays a critical role in recruiting leukocytes in inflammatory lesions by mediating leukocyte rolling on selectins. Core-2 O-glycosylation of a N-terminal threonine and sulfation of at least one tyrosine residue of PSGL-1 are required for L- and P-selectin binding. Little information is available on the intra- and inter-species evolution of PSGL-1 primary structure. In addition, the evolutionary conservation of selectin binding site on PSGL-1 has not been previously examined in detail. Therefore, we performed multiple sequence alignment of PSGL-1 amino acid sequences of 14 mammals (human, chimpanzee, rhesus monkey, bovine, pig, rat, tree-shrew, bushbaby, mouse, bat, horse, cat, sheep and dog) and examined mammalian PSGL-1 interactions with human selectins. RESULTS: A signal peptide was predicted in each sequence and a propeptide cleavage site was found in 9/14 species. PSGL-1 N-terminus is poorly conserved. However, each species exhibits at least one tyrosine sulfation site and, except in horse and dog, a T [D/E]PP [D/E] motif associated to the core-2 O-glycosylation of a N-terminal threonine. A mucin-like domain of 250-280 amino acids long was disclosed in all studied species. It lies between the conserved N-terminal O-glycosylated threonine (Thr-57 in human) and the transmembrane domain, and contains a central region exhibiting a variable number of decameric repeats (DR). Interspecies and intraspecies polymorphisms were observed. Transmembrane and cytoplasmic domain sequences are well conserved. The moesin binding residues that serve as adaptor between PSGL-1 and Syk, and are involved in regulating PSGL-1-dependent rolling on P-selectin are perfectly conserved in all analyzed mammalian sequences. Despite a poor conservation of PSGL-1 N-terminal sequence, CHO cells co-expressing human glycosyltransferases and human, bovine, pig or rat PSGL-1 efficiently rolled on human L- or P-selectin. By contrast, pig or rat neutrophils were much less efficiently recruited than human or bovine neutrophils on human selectins. Horse PSGL-1, glycosylated by human or equine glycosyltransferases, did not interact with P-selectin. In all five species, tyrosine sulfation of PSGL-1 was required for selectin binding. CONCLUSION: These observations show that PSGL-1 amino acid sequence of the transmembrane and cytoplasmic domains are well conserved and that, despite a poor conservation of PSGL-1 N-terminus, L- and P-selectin binding sites are evolutionary conserved. Functional assays reveal a critical role for post-translational modifications in regulating mammalian PSGL-1 interactions with selectins.

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P-selectin glycoprotein ligand-1 plays a crucial role in the selective recruitment of leukocytes into the atherosclerotic arterial wall.

Publications

P-selectin glycoprotein ligand-1 plays a crucial role in the selective recruitment of leukocytes into the atherosclerotic arterial wall.

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