SELL - selectin L |Elisa - Clia - Antibody - Protein

Background

Selectin L (SELL), commonly known as L-selectin, is a cell adhesion molecule that belongs to the selectin family, which includes three primary members: L-selectin (SELL), E-selectin (SELE), and P-selectin (SELP). L-selectin plays a crucial role in immune surveillance and inflammatory responses, primarily facilitating the interaction between leukocytes (white blood cells) and endothelial cells. SELL is expressed constitutively on most leukocytes, including neutrophils, monocytes, T lymphocytes, B lymphocytes, and natural killer (NK) cells. It is essential for the initial steps of leukocyte extravasation, where leukocytes migrate from the bloodstream to peripheral tissues to respond to infection or injury.

SELL mediates leukocyte rolling on the endothelium, an essential part of the immune cell recruitment cascade during inflammation and immune surveillance. It is involved in homing of lymphocytes to secondary lymphoid organs, such as lymph nodes, and facilitates the recruitment of leukocytes to sites of inflammation. SELL’s primary ligands include sialyl Lewis X (sLeX) and GlyCAM-1 (glycan-bearing cell adhesion molecule-1), which are expressed on endothelial cells. The role of L-selectin in trafficking leukocytes to lymphoid tissues is vital for maintaining immune homeostasis and responding to pathogens.

Protein Structure

L-selectin (SELL) is a transmembrane glycoprotein encoded by the SELL gene located on chromosome 1q24.2. The protein consists of 372 amino acids and has a molecular weight of approximately 74-100 kDa, depending on glycosylation. L-selectin, like other selectins, shares several conserved structural domains, including:

N-terminal C-type Lectin Domain:

• The N-terminal region of L-selectin contains a calcium-dependent (C-type) lectin domain, which is responsible for binding to sialylated carbohydrate ligands such as sLeX on glycoproteins of endothelial cells. This lectin domain facilitates the interaction between leukocytes and endothelial cells during leukocyte rolling and extravasation.

Epidermal Growth Factor (EGF)-like Domain:

• Adjacent to the lectin domain is an EGF-like domain. This domain provides structural support and contributes to stabilizing the interaction between L-selectin and its ligands. It is also involved in maintaining the correct conformation of the protein.

Complement Regulatory-like Repeats (CR Domains):

• L-selectin contains two short consensus repeat (SCR) domains or complement regulatory-like domains. These repeats are structurally similar to those found in proteins that regulate complement activation. The CR domains allow for flexibility in the protein structure, facilitating interactions with ligands at varying distances from the cell surface.

Transmembrane Domain:

• The transmembrane domain of L-selectin is a hydrophobic region that spans the lipid bilayer of the cell membrane, anchoring the molecule on the cell surface. It is essential for the stable localization of L-selectin on leukocytes and plays a role in signal transduction following ligand binding.

Cytoplasmic Tail:

• The intracellular (cytoplasmic) tail of L-selectin is relatively short, comprising 17 amino acids. This tail is critical for intracellular signaling, receptor trafficking, and shedding of L-selectin. Upon activation of leukocytes by inflammatory stimuli, the cytoplasmic domain participates in the cleavage of the extracellular domain by proteases, leading to L-selectin shedding. This shedding regulates the duration of L-selectin-mediated interactions and plays a role in modulating immune responses.

Post-Translational Modifications:

• L-selectin undergoes several post-translational modifications, including N-linked glycosylation, which is critical for its proper folding, stability, and ligand-binding capability. The glycosylation state of L-selectin can influence its affinity for ligands and its ability to mediate leukocyte-endothelial interactions.

Classification and Subtypes

L-selectin is classified as part of the selectin family, which includes:

L-selectin (SELL):

• Expressed on most leukocytes and involved in leukocyte rolling and homing to lymphoid tissues.

E-selectin (SELE):

• Expressed on activated endothelial cells during inflammation and mediates rolling of leukocytes along the endothelium.

P-selectin (SELP):

• Expressed on platelets and endothelial cells, involved in the interaction between platelets, endothelial cells, and leukocytes.

There are no known subtypes or isoforms of L-selectin, but its expression can be modulated by various inflammatory stimuli, and its shedding from the cell surface is regulated by proteolytic cleavage.

Function and Biological Significance

The primary function of L-selectin is to mediate leukocyte rolling on the endothelium, a critical step in leukocyte trafficking from the bloodstream to peripheral tissues. L-selectin also plays a key role in lymphocyte homing to secondary lymphoid organs such as lymph nodes and Peyer’s patches, ensuring immune surveillance and the initiation of immune responses.

Leukocyte Rolling:

• During inflammation, leukocytes in the bloodstream need to slow down and roll along the endothelial surface before they can adhere firmly and transmigrate into inflamed tissues. L-selectin binds to carbohydrate ligands such as GlyCAM-1, MadCAM-1 (mucosal addressin cell adhesion molecule-1), and CD34 on endothelial cells. These interactions are weak and reversible, enabling leukocytes to roll along the endothelium under the force of blood flow.

Lymphocyte Homing:

• L-selectin is essential for lymphocyte recirculation through secondary lymphoid tissues. It interacts with peripheral lymph node addressin (PNAd) on high endothelial venules (HEVs) in lymph nodes, facilitating the entry of naïve T cells and B cells into lymphoid organs, where they can encounter antigens and initiate adaptive immune responses.

Immune Surveillance:

• L-selectin plays a role in immune surveillance by helping leukocytes patrol blood vessels and detect sites of inflammation or infection. It facilitates the recruitment of neutrophils and monocytes to inflamed tissues, where they participate in pathogen clearance and tissue repair.

L-selectin Shedding:

• Upon leukocyte activation, metalloproteases cleave the extracellular domain of L-selectin, leading to its shedding from the cell surface. This process regulates the intensity and duration of leukocyte rolling and influences the transition from rolling to firm adhesion. Shedding of L-selectin also impacts immune cell trafficking and responsiveness during inflammation.

Clinical Issues

L-selectin dysfunction or dysregulation is implicated in several disease processes:

Autoimmune Diseases:

• In conditions such as multiple sclerosis and rheumatoid arthritis, abnormal leukocyte trafficking mediated by L-selectin contributes to tissue inflammation and damage. Targeting L-selectin interactions could be a therapeutic approach to modulating immune cell migration and reducing autoimmune responses.

Cancer Metastasis:

• L-selectin has been implicated in the metastasis of certain cancers. Tumor cells may exploit L-selectin-mediated mechanisms to adhere to the endothelium and migrate to secondary sites. Inhibiting L-selectin interactions could potentially reduce the metastatic potential of circulating tumor cells.

Leukocyte Adhesion Deficiency (LAD):

• Defects in L-selectin function or expression can lead to impaired leukocyte trafficking and predispose individuals to recurrent infections. LAD is a rare immunodeficiency disorder characterized by poor leukocyte adhesion and defective immune responses.

Cardiovascular Diseases:

• Elevated levels of soluble L-selectin have been associated with atherosclerosis and other inflammatory cardiovascular conditions. Increased L-selectin expression promotes leukocyte recruitment to the endothelium, contributing to vascular inflammation and plaque formation.

Transplant Rejection:

• L-selectin plays a role in the immune response to transplanted tissues. Blocking L-selectin interactions can reduce leukocyte infiltration into graft tissues and may help prevent graft rejection in transplant patients.

Summary

L-selectin (SELL) is a key cell adhesion molecule expressed on leukocytes, which mediates leukocyte rolling, lymphocyte homing, and immune surveillance. Structurally, L-selectin consists of a C-type lectin domain, EGF-like domain, and complement regulatory-like repeats, with a transmembrane domain anchoring it to the cell membrane. Its primary function is to mediate the initial stages of leukocyte recruitment to sites of inflammation and to guide lymphocytes to secondary lymphoid tissues. L-selectin plays significant roles in autoimmune diseases, cancer metastasis, cardiovascular inflammation, and transplant rejection. Understanding its molecular mechanisms and the regulation of its shedding provides insight into therapeutic strategies for controlling immune responses and inflammation.