ITGAL - integrin subunit alpha L |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha L (ITGAL), also known as CD11a, is a protein encoded by the ITGAL gene in humans. This protein forms a part of the integrin family, which is a group of cell surface receptors that mediate various biological processes, including immune cell adhesion, migration, and signaling. ITGAL pairs with the integrin beta-2 subunit (CD18) to form the LFA-1 (lymphocyte function-associated antigen 1), a heterodimeric receptor crucial for immune responses.

ITGAL’s primary role is in the immune system, where it facilitates cell-cell adhesion during the immune response, helping lymphocytes, neutrophils, and other leukocytes adhere to other cells, such as endothelial cells, antigen-presenting cells, and target cells. This integrin is particularly critical in the homing, trafficking, and activation of immune cells, including T cells, natural killer (NK) cells, and neutrophils. ITGAL mediates interactions between leukocytes and the vascular endothelium by binding to intercellular adhesion molecules (ICAMs), which are vital for immune surveillance and the body's response to infection and inflammation.

Protein Structure

The ITGAL protein, or integrin alpha L, is a transmembrane glycoprotein that is composed of approximately 1,182 amino acids. Its structure is organized into several distinct domains, each of which contributes to the overall function of the protein.

Extracellular Region:

• The majority of the protein is an extracellular domain (~ 1,072 amino acids), responsible for binding to ligands such as ICAMs (ICAM-1, ICAM-2, and ICAM-3).
• The extracellular portion includes seven tandemly arranged beta-propeller domains at the N-terminus, which are characteristic of alpha integrin subunits. These propeller structures form the ligand-binding region of the protein.
• A key feature of the alpha L subunit is the I (inserted) domain, which is inserted into the beta-propeller structure. The I-domain is essential for binding to the immunoglobulin superfamily molecules (e.g., ICAMs). This domain adopts a Rossmann fold, which is stabilized by metal ion-dependent adhesion site (MIDAS) motifs that coordinate divalent cations, critical for ligand binding and integrin activation.
• The thigh domain and calf-1 and calf-2 domains are involved in stabilizing the molecule and contributing to the flexibility needed for ligand interaction.

Transmembrane Domain:

• The transmembrane region of ITGAL is a single alpha-helical domain that anchors the protein into the cell membrane. The alpha L chain pairs non-covalently with the beta-2 chain (CD18) in the membrane to form the functional heterodimer.

Cytoplasmic Tail:

• The short cytoplasmic domain (~20 amino acids) is involved in inside-out signaling, where intracellular signals modify the integrin's extracellular affinity for ligands. The cytoplasmic tail also participates in outside-in signaling, where extracellular events trigger intracellular signaling cascades that affect cellular responses such as migration, adhesion, and actin cytoskeleton remodeling.

Classification and Subtypes

ITGAL belongs to the integrin family, which is classified based on the alpha and beta subunits that form the integrin heterodimers. There are 18 alpha subunits and 8 beta subunits in humans, which combine to form 24 different integrin receptors.

ITGAL is classified specifically under the beta-2 integrin subfamily (also known as the leukocyte integrins) due to its pairing with the beta-2 subunit (CD18). This subfamily is exclusive to leukocytes and includes four key integrins:

• LFA-1 (αLβ2, CD11a/CD18) – Involved in leukocyte adhesion and migration.
• Mac-1 (αMβ2, CD11b/CD18) – Involved in phagocytosis and immune response.
• p150,95 (αXβ2, CD11c/CD18) – Functions in antigen presentation and immune regulation.
• αDβ2 (CD11d/CD18) – Plays a role in monocyte and macrophage adhesion.

Each of these integrins, including LFA-1, plays a unique role in immune surveillance, inflammation, and pathogen clearance.

Function and Biological Significance

ITGAL, through its involvement in forming LFA-1 (αLβ2), plays a central role in immune system functioning. Its primary functions include:

1. Leukocyte Adhesion and Migration: LFA-1 binds to ICAMs on endothelial cells, facilitating leukocyte extravasation during inflammation. This allows immune cells to migrate from the bloodstream into tissues where an immune response is needed. The interaction between LFA-1 and ICAMs is essential for the arrest and firm adhesion of leukocytes on the endothelial surface, a key step in immune surveillance and inflammation.
2. T-Cell Activation and Immune Synapse Formation: LFA-1 is critical for T-cell activation by antigen-presenting cells (APCs). When T cells recognize antigens presented by MHC molecules on APCs, LFA-1 binds to ICAMs on the surface of the APCs to form a stable interaction known as the immune synapse. This synapse ensures prolonged contact between T cells and APCs, enhancing the signaling required for T-cell activation and proliferation.
3. Cytotoxic Activity of NK Cells and T Cells: ITGAL is also involved in the function of cytotoxic T cells and natural killer (NK) cells. By binding to ICAM-1 on target cells, LFA-1 helps NK cells and cytotoxic T cells adhere to and eliminate virus-infected or malignant cells.
4. Immune Homeostasis: Beyond its role in acute immune responses, LFA-1 helps regulate immune homeostasis by mediating interactions between different types of leukocytes. It assists in the formation of cell clusters that are important for regulating the activity of immune cells in various tissues, ensuring a balanced immune response.

Clinical Significance

Given its central role in immune cell adhesion and signaling, aberrations in ITGAL function can lead to a variety of clinical conditions:

1. Leukocyte Adhesion Deficiency (LAD) Type I: This genetic disorder is caused by mutations in the ITGB2 gene (which encodes the beta-2 subunit), leading to defective LFA-1 function. Patients with LAD suffer from recurrent bacterial infections due to their leukocytes' inability to adhere properly and migrate into tissues.
2. Autoimmune Diseases: Dysregulated ITGAL expression or function is associated with autoimmune diseases like rheumatoid arthritis and multiple sclerosis. In these conditions, excessive or inappropriate leukocyte adhesion and migration into tissues can contribute to chronic inflammation and tissue damage.
3. Cancer: ITGAL may play a role in cancer immunity by facilitating the interaction between immune cells and tumor cells. LFA-1/ICAM interactions are critical for immune cell-mediated tumor destruction. Conversely, cancer cells may exploit integrin signaling pathways to escape immune surveillance or promote metastasis.
4. Therapeutic Targeting: ITGAL and LFA-1 have become therapeutic targets for modulating immune responses. Drugs like efalizumab, a monoclonal antibody against LFA-1, have been used to treat conditions like psoriasis by inhibiting immune cell adhesion and reducing inflammation. Other integrin inhibitors are under investigation for their potential in treating autoimmune diseases and certain types of cancer.

Summary

ITGAL, or integrin alpha L, plays a crucial role in the immune system as a subunit of the LFA-1 integrin. Its structure, comprising extracellular, transmembrane, and cytoplasmic domains, allows it to mediate leukocyte adhesion, migration, and immune responses. By interacting with ICAMs, ITGAL is critical for immune cell trafficking, T-cell activation, and immune surveillance. Dysregulation of ITGAL is implicated in various clinical conditions, including autoimmune diseases and immune deficiencies, making it a significant target for therapeutic intervention. Through its involvement in both normal immune responses and pathological conditions, ITGAL remains a key focus of research in immunology and therapeutic development.