ITGAM - integrin subunit alpha M |Elisa - Clia - Antibody - Protein

Background

ITGAM (integrin subunit alpha M), also known as CD11b, is a protein encoded by the ITGAM gene in humans. It is a member of the integrin family, which is a group of transmembrane receptors involved in cell adhesion and signal transduction. ITGAM specifically combines with the integrin beta 2 subunit (CD18) to form Mac-1 (macrophage-1 antigen), also referred to as αMβ2 or CR3 (complement receptor 3). This integrin is primarily expressed on myeloid cells such as monocytes, macrophages, neutrophils, and natural killer (NK) cells, and plays a pivotal role in the immune system.

The primary function of ITGAM/Mac-1 is to mediate the adhesion of leukocytes to various surfaces, enabling the cells to migrate toward sites of infection or injury. ITGAM is critical for functions such as phagocytosis, immune surveillance, and complement-mediated immune responses. It also participates in the regulation of inflammation and tissue repair. Given its involvement in these critical immune processes, ITGAM has been extensively studied for its role in both physiological immune responses and pathological conditions such as autoimmune diseases and chronic inflammation.

Protein Structure

ITGAM, or integrin alpha M, is a large transmembrane glycoprotein consisting of approximately 1,127 amino acids. Like other integrins, it is made up of distinct structural domains that are essential for its function.

Extracellular Region:

The extracellular region comprises most of the ITGAM molecule (~1,086 amino acids) and is primarily responsible for ligand binding. This domain is divided into several subdomains:

• Alpha I (inserted) domain: One of the most functionally important regions of ITGAM, the I domain binds to ligands such as complement component C3bi, intercellular adhesion molecules (ICAM-1, ICAM-2), fibrinogen, and other proteins involved in the immune response. This domain adopts a Rossmann fold stabilized by the metal ion-dependent adhesion site (MIDAS), a region that coordinates divalent cations (usually Mg²⁺ or Mn²⁺) required for ligand binding.
• Beta-propeller domain: Located at the N-terminal portion of the extracellular region, this domain consists of seven beta-sheet structures that form a propeller-like shape. It interacts with the beta-2 integrin subunit (CD18) and contributes to ligand specificity.

Thigh and calf-1/calf-2 domains: These domains are located near the membrane-proximal region of the extracellular domain and are thought to contribute to the overall stability and flexibility of the protein. They undergo conformational changes during integrin activation, influencing . how ITGAM interacts with its ligands.

Transmembrane Domain:

• ITGAM has a short transmembrane alpha-helix that anchors the integrin in the cell membrane. This region plays a key role in integrin dimerization, as the alpha M and beta 2 subunits pair within the membrane to form a functional receptor complex. The transmembrane region is involved in the regulation of integrin activation, helping to transmit mechanical signals across the membrane.

Cytoplasmic Tail:

• The cytoplasmic domain of ITGAM is relatively short (~20 amino acids) but is crucial for intracellular signaling. It mediates "inside-out" signaling, where intracellular signaling pathways affect the integrin's affinity for its extracellular ligands. Additionally, it plays a role in "outside-in" signaling, where ligand binding triggers intracellular responses, including changes in the cytoskeleton and the initiation of signal transduction pathways that regulate immune cell activity, migration, and adhesion.

Classification and Subtypes

ITGAM belongs to the integrin family, which is composed of receptors that mediate cell-cell and cell-matrix interactions. Integrins are heterodimeric, consisting of an alpha and beta subunit, and are categorized based on the alpha subunit they contain.

ITGAM pairs with beta-2 integrin subunit (CD18) to form the heterodimer Mac-1 (αMβ2 integrin). ITGAM is part of the beta-2 integrin subfamily, also referred to as leukocyte integrins, as they are predominantly expressed on white blood cells (leukocytes). Other members of this subfamily include:

• LFA-1 (αLβ2, CD11a/CD18): Plays a role in T-cell activation and leukocyte adhesion.
• p150,95 (αXβ2, CD11c/CD18): Involved in antigen presentation and phagocytosis.
• αDβ2 (CD11d/CD18): Primarily expressed on macrophages and monocytes, involved in cell adhesion and migration.

The beta-2 integrins, including Mac-1, are integral to immune cell interactions with other cells and the extracellular matrix, contributing to processes such as phagocytosis, chemotaxis, and the inflammatory response.

Function and Biological Significance

ITGAM is a multifunctional integrin with significant roles in the immune response, primarily through its activity as a component of the Mac-1 (CR3) receptor. Key functions of ITGAM include:

1. Phagocytosis: ITGAM is involved in opsonization-mediated phagocytosis, a process where immune cells such as macrophages and neutrophils engulf and digest pathogens or cellular debris. ITGAM, through its ability to bind to complement component C3bi, allows phagocytic cells to recognize and ingest particles coated with this complement fragment, enhancing the clearance of pathogens and apoptotic cells.
2. Leukocyte Adhesion and Migration: ITGAM plays a key role in mediating adhesion of leukocytes to the endothelium and extracellular matrix during inflammation. By interacting with ICAM-1 and other adhesion molecules, ITGAM helps immune cells migrate from the bloodstream into tissues where they are needed. This process is critical for immune surveillance, wound healing, and responding to infections.
3. Inflammatory Response: ITGAM is involved in the regulation of inflammation. It participates in the recruitment of neutrophils and other immune cells to sites of tissue injury or infection. Additionally, Mac-1 mediates the adhesion of neutrophils to activated endothelial cells, a key step in the inflammatory cascade. This function is critical in conditions such as sepsis, where immune cells must be rapidly recruited to sites of infection.
4. Complement Receptor Activity: As a component of the complement receptor 3 (CR3), ITGAM is directly involved in recognizing pathogens opsonized by complement proteins, particularly C3bi. This recognition facilitates the engulfment and destruction of pathogens, making ITGAM crucial in the innate immune response.
5. Immune Regulation and Tissue Repair: ITGAM also plays a role in tissue remodeling and repair. It regulates immune cell interaction with the extracellular matrix, influencing processes like wound healing and resolution of inflammation. By controlling immune cell adhesion, migration, and cytokine production, ITGAM helps balance pro-inflammatory and anti-inflammatory signals during tissue repair.

Clinical Issues

Given its fundamental role in immune cell function, alterations in ITGAM activity are associated with several clinical conditions:

1. Autoimmune Diseases: Mutations or dysregulation of ITGAM have been linked to autoimmune disorders such as systemic lupus erythematosus (SLE). Polymorphisms in the ITGAM gene have been found to increase susceptibility to lupus, potentially by altering the regulation of immune responses and inflammation.
2. Chronic Inflammatory Diseases: Overactivity of ITGAM can lead to excessive recruitment of leukocytes, contributing to chronic inflammatory conditions such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). In these conditions, ITGAM-mediated leukocyte adhesion and migration exacerbate inflammation, leading to tissue damage.
3. Sepsis: In severe infections, such as sepsis, ITGAM plays a critical role in the immune system's response to pathogens. Excessive activation of ITGAM can lead to hyperinflammation and tissue damage, making it a potential target for therapies aimed at modulating the immune response during sepsis.
4. Therapeutic Targeting: ITGAM is a potential therapeutic target for controlling excessive inflammation and immune responses. Inhibitors of ITGAM/Mac-1 are being explored for their potential to reduce inflammation in autoimmune diseases, while enhancing its function could be beneficial in boosting immune responses to infections or cancer.

Summary

ITGAM (integrin alpha M) is a crucial component of the Mac-1 (CR3) integrin, involved in immune cell adhesion, migration, and phagocytosis. Its protein structure includes an extensive extracellular region responsible for ligand binding, a transmembrane domain for anchoring the integrin to the cell membrane, and a short cytoplasmic tail involved in signal transduction. Functionally, ITGAM regulates a wide range of immune responses, including complement-mediated phagocytosis, leukocyte migration, and inflammation control. Dysregulation of ITGAM is implicated in autoimmune diseases, chronic inflammation, and sepsis, making it a valuable target for therapeutic interventions. Understanding ITGAM's role in the immune system continues to inform research on immune regulation and potential treatments for immune-related diseases.