SELs
Selectins are characterized by an extracellular N-terminal domain related to sugar-binding mammalian lectins, consist of:
E-selectin (SELE or CD62E, previously ELAM-1), which is confined to endothelium;
P-selectin (SELP or CD62P, previously GMP140 or PADGEM), which is present in endothelium and platelets;
L-selectin (SELL or CD62L, previously LAM-1), which is expressed on most leukocyte types (Box 2-1).
Selectins bind, through their lectin domain, to sialylated forms of oligosaccharides (e.g., sialylated Lewis X), which themselves are covalently bound to various mucin-like glycoproteins: GlyCAM-1, SELPLG (PSGL-1), GLG1 (ESL-1), and CD34.
Structure
The selectins (SELs) are a family of three closely related proteins that differ in their cellular distribution but all function in adhesion of leukocytes to endothelial cells.
All selectins are single-chain transmembrane glycoproteins with an amino terminus that is related to carbohydrate-binding proteins known as C-type lectins. Like other C-type lectins, ligand binding by selectins is calcium-dependent (hence the name C-type).
The binding of selectins to their ligands has a fast on rate but also has a fast off rate and is of low affinity; this property allows selectins to mediate initial attachment and subsequent rolling of leukocytes on endothelium in the face of flowing blood.
L-selectin (SELL), or CD62L, is expressed on lymphocytes and other leukocytes. It serves as a homing receptor for lymphocytes to enter lymph nodes by binding to high endothelial venules (HEVs).
SELL also serves to bind neutrophils to cytokine-activated endothelial cells at sites of inflammation. L-selectin is located on the tips of microvillus projections of leukocytes, facilitating its interaction with ligands on endothelium.
At least three endothelial cell ligands can bind L-selectin-glycan-bearing cell adhesion molecule-1 (GlyCAM-1), a secreted proteoglycan found on HEVs of lymph node; mucosal addressin cell adhesion molecule-1 (MadCAM-1), expressed on endothelial cells in gut-associated lymphoid tissues; and CD34, a proteoglycan on endothelial cells (and bone marrow cells).
The protein backbones of all these ligands are modified by specific carbohydrates, which are the molecules actually recognized by the selectin.
E-selectin (SELE), or CD62E, previously known as endothelial leukocyte adhesion molecule-1 (ELAM1), is expressed only on cytokine-activated endothelial cells, hence the designation E.
E-selectin recognizes complex sialylated carbohydrate groups related to the Lewis X or Lewis A family found on various surface proteins of granulocytes, monocytes, and previously activated effector and memory T cells.
E-selectin is important in the homing of effector and memory T cells to some peripheral sites of inflammation, particularly in the skin. Endothelial cell expression of E-selectin is a hallmark of acute cytokine-mediated inflammation, and antibodies to E-selectin can block leukocyte accumulation in vivo.
P-selectin (SELP) (CD62P) was first identified in the secretory granules of platelets, hence the designation P. It has since been found in secretory granules of endothelial cells, called Weibel-Palade bodies.
When endothelial cells or platelets are stimulated, P-selectin is translocated within minutes to the cell surface. On reaching the cell surface, P-selectin mediates binding of neutrophils, T lymphocytes, and monocytes. The complex carbohydrate ligands recognized by P-selectin appear similar to those recognized by E-selectin.
Pathology
Humans who lack one of the enzymes needed to express the carbohydrate ligands for E-selectin (SELE) and P-selectin (SELP) on neutrophils have similar problems, resulting in a syndrome called leukocyte adhesion deficiency type 2 (LAD2) (MIM.266265). The disorder (CDG type IIc) is caused by mutation in the gene encoding GDP-fucose transporter-1 (FUCT1) (MIM.605881).
(NB: LAD1 is a deficiency of ITGB2 or CD18 or LFA-1.)
Animal models
Knockout mice
The essential physiologic roles of selectins have been reinforced by studies of gene knockout mice. L-selectin-deficient mice have small, poorly formed lymph nodes with few T cells. Mice lacking either E-selectin or P-selectin have only mild defects in leukocyte recruitment, suggesting that these two molecules are functionally redundant.
Double knockout mice lacking both E-selectin (SELE) and P-selectin (SELP) have significantly impaired leukocyte recruitment and increased susceptibility to infections.
See also
SELE: E-selectin (MIM.131210)
SELL: L-selectin (MIM.153240)
SELP: P-selectin (MIM.173610)
References
Ley K. The role of selectins in inflammation and disease. Trends Mol Med. 2003 Jun;9(6):263-8. PMID: #12829015#