SELP - selectin P |Elisa - Clia - Antibody - Protein

Background

Selectin P (SELP), also known as P-selectin, is a cell adhesion molecule that plays a key role in inflammation, hemostasis, and immune response by mediating the interaction between platelets, endothelial cells, and leukocytes. P-selectin is primarily stored in the alpha granules of platelets and the Weibel-Palade bodies of endothelial cells and is rapidly mobilized to the cell surface upon cellular activation. The SELP gene, which encodes P-selectin, is located on chromosome 1q24.2. It belongs to the selectin family, which includes L-selectin (SELL), E-selectin (SELE), and P-selectin (SELP), all of which are involved in the early stages of leukocyte trafficking during inflammatory responses.

P-selectin functions in the rolling and adhesion of leukocytes to the endothelium, a critical step in immune surveillance and the recruitment of immune cells to sites of tissue damage or infection. In the context of inflammation, it facilitates the rapid interaction between leukocytes and the vascular wall, allowing for their migration into the affected tissue. Its ligands include P-selectin glycoprotein ligand-1 (PSGL-1), which is found on the surface of leukocytes. P-selectin's involvement in thrombus formation is also crucial, as it mediates interactions between activated platelets and the endothelium, contributing to thrombosis.

Protein Structure

P-selectin is a 140 kDa transmembrane glycoprotein composed of several distinct structural domains that enable its adhesion and signaling functions. The P-selectin protein has a unique modular architecture, including the following domains:

N-terminal Lectin-like Domain:

• The N-terminus of P-selectin contains a C-type lectin domain, which is responsible for binding to specific carbohydrate structures, such as sialyl Lewis X (sLeX), that are presented on ligands like PSGL-1 on leukocytes. This domain's function is calcium-dependent, meaning that it requires calcium ions to bind effectively to its ligand.

Epidermal Growth Factor (EGF)-like Domain:

• Adjacent to the lectin domain is an EGF-like domain, which provides structural support and stability to the protein. This domain helps maintain the proper conformation of the selectin and enhances its ability to interact with ligands.

Complement-binding Protein-like Repeats:

• P-selectin contains nine complement control protein (CCP) domains or short consensus repeats (SCRs). These domains are structurally similar to those found in complement regulatory proteins. The SCRs extend the lectin domain from the cell surface, allowing P-selectin to interact with circulating leukocytes in the bloodstream even under high shear stress conditions.

Transmembrane Domain:

• The transmembrane region anchors P-selectin to the plasma membrane of either platelets or endothelial cells. This domain spans the lipid bilayer and ensures that P-selectin remains properly localized on the cell surface following activation.

Cytoplasmic Tail:

• The cytoplasmic tail of P-selectin is relatively short, consisting of approximately 35 amino acids. This tail is involved in intracellular signaling and plays a role in the trafficking and storage of P-selectin within Weibel-Palade bodies and alpha granules. Upon cellular activation, vesicular trafficking mechanisms deliver P-selectin to the plasma membrane, where it becomes functional.

Post-translational Modifications:

• P-selectin is a glycoprotein, meaning that it is heavily glycosylated. This glycosylation is crucial for its ligand-binding capabilities, particularly in recognizing carbohydrate structures on its ligands. Additionally, phosphorylation of the cytoplasmic tail plays a role in its intracellular trafficking and storage.

Classification and Subtypes

P-selectin (SELP) is one of the three members of the selectin family, along with:

L-selectin (SELL):

• Found on leukocytes, responsible for leukocyte rolling and homing to lymphoid tissues.

E-selectin (SELE):

• Expressed on activated endothelial cells, involved in leukocyte recruitment during inflammation.

P-selectin (SELP):

• Expressed on activated platelets and endothelial cells, involved in inflammation and thrombosis.

P-selectin does not have subtypes, but its activity is modulated by cellular activation and post-translational modifications. The rapid translocation of P-selectin to the cell surface following activation is critical for its role in acute inflammatory responses and platelet function.

Function and Biological Significance

P-selectin plays several pivotal roles in inflammation, immune response, and hemostasis. Its main functions include:

Leukocyte Rolling and Adhesion:

• P-selectin mediates the initial rolling of leukocytes on the endothelial surface during inflammation. By interacting with PSGL-1 on leukocytes, it slows down the movement of these immune cells, allowing them to tether and roll along the endothelium. This is the first step in leukocyte extravasation, which leads to the migration of leukocytes into tissues to combat infections or respond to injury.

Platelet-endothelium Interaction:

• P-selectin is expressed on activated platelets, where it facilitates interactions with endothelial cells and leukocytes. This interaction is crucial for the formation of platelet-leukocyte aggregates and the recruitment of immune cells to sites of vascular injury.

Thrombosis:

• P-selectin plays a significant role in thrombus formation. It mediates the adhesion of platelets to the endothelial surface and to other platelets, which is an essential step in the development of blood clots. By promoting platelet aggregation, P-selectin contributes to the stabilization of thrombi, especially in high-shear environments like arteries.

Immune Response:

• In addition to its role in inflammation and thrombosis, P-selectin is involved in immune surveillance. By facilitating the migration of leukocytes to peripheral tissues, it helps ensure that immune cells can reach sites of infection or damage to initiate immune responses.

P-selectin Shedding:

• After activation, a portion of membrane-bound P-selectin can be cleaved and released into circulation as soluble P-selectin (sP-selectin). The levels of sP-selectin are often used as a marker of endothelial activation or platelet activation, and elevated levels are associated with various disease states, including cardiovascular disease.

Clinical Issues

P-selectin is involved in several pathological conditions due to its roles in inflammation, thrombosis, and immune cell trafficking:

Cardiovascular Disease:

• Elevated levels of soluble P-selectin have been associated with a higher risk of atherosclerosis and thrombotic events such as myocardial infarction and stroke. P-selectin facilitates the recruitment of leukocytes to atherosclerotic plaques, promoting inflammation and plaque instability, which can lead to acute cardiovascular events.

Venous Thromboembolism (VTE):

• P-selectin is implicated in the formation of venous thrombi by mediating interactions between activated platelets, leukocytes, and the vascular endothelium. Inhibiting P-selectin function has been explored as a therapeutic strategy to reduce the risk of deep vein thrombosis (DVT) and pulmonary embolism.

Inflammatory Diseases:

• P-selectin plays a role in the pathogenesis of several chronic inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease (IBD), and asthma. In these conditions, P-selectin-mediated recruitment of leukocytes to inflamed tissues exacerbates the inflammatory response and contributes to tissue damage.

Cancer Metastasis:

• P-selectin has been implicated in the metastatic spread of certain cancers. Tumor cells that express ligands for P-selectin can adhere to activated platelets and endothelial cells, facilitating their movement through the bloodstream and enhancing their ability to establish secondary tumors in distant organs.

Therapeutic Targeting:

• Due to its central role in inflammation and thrombosis, P-selectin is a potential therapeutic target. P-selectin inhibitors are being explored for their ability to reduce inflammation, prevent thrombus formation, and mitigate the progression of atherosclerosis. Crizanlizumab, a monoclonal antibody against P-selectin, has been approved for reducing the frequency of vaso-occlusive crises in patients with sickle cell disease.

Summary

P-selectin (SELP) is a key cell adhesion molecule involved in leukocyte recruitment, thrombosis, and immune surveillance. It is stored in platelets' alpha granules and endothelial cells' Weibel-Palade bodies, rapidly translocating to the cell surface upon activation. Structurally, P-selectin consists of a C-type lectin domain, EGF-like domain, and complement control protein repeats, which facilitate its interaction with ligands such as PSGL-1 on leukocytes. P-selectin plays a critical role in inflammation by mediating leukocyte rolling and adhesion, and in thrombosis by promoting platelet aggregation and interactions with the endothelium. Elevated levels of soluble P-selectin are associated with cardiovascular diseases, venous thromboembolism, and chronic inflammatory conditions. As a therapeutic target, P-selectin inhibition shows promise in treating diseases characterized by excessive inflammation and thrombosis, such as atherosclerosis and sickle cell disease.