ITGA4 - integrin subunit alpha 4 |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha 4 (ITGA4) is a critical member of the integrin family of cell surface receptors, which mediate cell-cell and cell-extracellular matrix (ECM) interactions. ITGA4 pairs with different beta subunits to form heterodimeric receptors that facilitate various biological processes, including immune cell migration, inflammation, tissue development, and cell adhesion. ITGA4 predominantly forms heterodimers with integrin beta 1 (ITGB1) to create the α4β1 integrin, also known as very late antigen-4 (VLA-4), and with integrin beta 7 (ITGB7) to form the α4β7 integrin. These integrins are particularly important in the immune system, where they mediate leukocyte adhesion and migration across blood vessels and into inflamed tissues.

The ITGA4 gene is located on chromosome 2q31.3, encoding a protein that is broadly expressed in immune cells, including T cells, B cells, monocytes, and eosinophils, as well as in certain endothelial and smooth muscle cells. ITGA4 plays a critical role in the immune response by guiding the migration of leukocytes into tissues during inflammation. Dysregulation of ITGA4 expression or function is linked to several inflammatory and autoimmune diseases, including multiple sclerosis, Crohn's disease, and asthma.

Protein Structure

ITGA4 is a type I transmembrane glycoprotein, with a structure typical of integrin alpha subunits. The protein is composed of approximately 1016 amino acids, including distinct extracellular, transmembrane, and cytoplasmic regions.

Extracellular Domain:

The extracellular domain of ITGA4 constitutes the majority of the protein and is responsible for ligand binding. This domain is composed of several important regions, including:

• β-propeller domain: Composed of seven blades, this domain facilitates specific recognition and binding of ligands such as vascular cell adhesion molecule 1 (VCAM-1) and fibronectin. The β-propeller domain provides ligand specificity and interacts with the ligand-binding site on the beta subunit.
• I-like domain: Present in some integrin alpha subunits, this domain plays a key role in ligand binding in the context of integrins that contain an I-domain. However, ITGA4 lacks an I-domain, and instead, ligand recognition occurs through its β-propeller domain in combination with the I-like domain of the integrin beta subunit.
• Calcium-binding sites: Divalent cations such as calcium (Ca²⁺) and magnesium (Mg²⁺) are critical for integrin activation and structural integrity. These cations stabilize the extracellular domain and enhance the ligand-binding affinity of ITGA4.

Transmembrane Domain:

• The transmembrane domain of ITGA4 is composed of a single α-helix spanning the plasma membrane. This domain plays a vital role in the heterodimerization of ITGA4 with beta subunits, particularly ITGB1 or ITGB7. The transmembrane region is also important for signal transduction across the membrane, facilitating communication between the extracellular environment and the intracellular signaling machinery.

Cytoplasmic Domain:

• The cytoplasmic tail of ITGA4 is relatively short, consisting of around 20-30 amino acids, but it plays a critical role in inside-out and outside-in signaling. This region lacks intrinsic enzymatic activity but interacts with intracellular proteins involved in cytoskeletal organization and integrin activation, such as talin and kindlin. The cytoplasmic domain also coordinates with the beta subunit’s cytoplasmic tail to regulate the affinity state of the integrin for its ligands.
• Phosphorylation of specific residues within the cytoplasmic domain of ITGA4 can modulate its interaction with intracellular signaling proteins and control the integrin's ability to mediate adhesion, migration, and signal transduction.

Heterodimerization:

• ITGA4 forms functional heterodimers primarily with ITGB1 (α4β1, VLA-4) or ITGB7 (α4β7). Dimerization is essential for the integrin to adopt its active conformation, enabling ligand binding and subsequent signaling events. Both heterodimers are involved in different immune cell functions, with α4β1 playing a key role in leukocyte migration across the endothelial barrier and α4β7 in gut-associated lymphoid tissue.

Classification and Subtypes

Integrins are categorized based on their alpha and beta subunit pairings, which determine their ligand specificity and functional roles. ITGA4 belongs to the alpha integrin subunit family and can pair with either ITGB1 or ITGB7, leading to the formation of the α4β1 integrin and α4β7 integrin, respectively. These two major subtypes differ in their ligand preferences and biological functions:

α4β1 Integrin (VLA-4):

• This integrin subtype is a receptor for VCAM-1, expressed on endothelial cells, and for fibronectin, an ECM protein. VLA-4 mediates leukocyte adhesion to the vascular endothelium, facilitating the transmigration of immune cells into inflamed tissues. It plays a central role in immune surveillance and the inflammatory response.

α4β7 Integrin:

• α4β7 primarily binds to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), which is expressed on high endothelial venules in gut-associated lymphoid tissues. This integrin is crucial for the homing of lymphocytes to the gut and plays a role in the immune response in intestinal tissues.

Function and Biological Significance

ITGA4-containing integrins are essential for several biological processes, particularly within the immune system. The primary functions of α4β1 and α4β7 integrins involve cell adhesion, migration, and immune cell trafficking, making ITGA4 critical in the context of immune surveillance, inflammation, and tissue repair.

Leukocyte Adhesion and Migration:

• ITGA4 mediates the adhesion of leukocytes (e.g., T cells, monocytes) to endothelial cells through interaction with VCAM-1. This adhesion is a key step in leukocyte extravasation, where immune cells migrate from the bloodstream into tissues, especially during inflammatory responses. α4β1 integrin facilitates leukocyte movement across the endothelium in response to chemotactic signals.
• In the gut, α4β7 integrin plays a similar role by mediating the homing of lymphocytes to gut-associated lymphoid tissues, ensuring proper immune surveillance in the gastrointestinal tract.

Immune Response Modulation:

• By regulating leukocyte trafficking, ITGA4 integrins are pivotal in modulating the immune response to infections and injuries. They influence the localization and activation of immune cells, including T cells, during an immune response.

Developmental Roles:

• ITGA4 is important in embryonic development, particularly in the formation of the placenta and the central nervous system. Mice lacking ITGA4 show severe defects in the development of the placenta and heart, underscoring its role in angiogenesis and vascular remodeling during development.

Tumor Biology:

• ITGA4 also plays a role in tumor progression and metastasis. It facilitates the adhesion of tumor cells to the ECM and the endothelium, promoting invasion and metastatic dissemination. In cancers such as melanoma and leukemia, upregulation of ITGA4 can enhance the migratory and invasive properties of tumor cells.

Clinical Issues

Autoimmune Diseases:

• ITGA4 has been implicated in the pathogenesis of several autoimmune and inflammatory disorders, including multiple sclerosis (MS), Crohn's disease, and rheumatoid arthritis. In these conditions, ITGA4-mediated leukocyte migration contributes to chronic inflammation in affected tissues. Therapeutic blockade of ITGA4 (using monoclonal antibodies like natalizumab) has been shown to reduce leukocyte infiltration and alleviate symptoms in these diseases.

Multiple Sclerosis (MS):

• In MS, ITGA4 mediates the migration of immune cells across the blood-brain barrier, contributing to inflammation and demyelination in the central nervous system. Natalizumab, an anti-α4 integrin antibody, is used to prevent immune cell trafficking into the brain, reducing MS relapses.

Inflammatory Bowel Disease (IBD):

• In Crohn's disease and ulcerative colitis, α4β7 integrin plays a key role in directing immune cells to the gut, contributing to intestinal inflammation. Blocking α4β7 with vedolizumab has proven effective in reducing gut inflammation in these patients.

Asthma:

• Elevated levels of ITGA4 expression on eosinophils and T cells have been associated with allergic asthma, contributing to airway inflammation and hyperresponsiveness. Targeting ITGA4 integrins is a potential therapeutic strategy for modulating inflammation in allergic diseases.

Summary

ITGA4, a vital integrin subunit, functions as part of the α4β1 and α4β7 integrins, playing essential roles in cell adhesion, migration, and immune responses. Structurally, ITGA4 contains an extracellular domain for ligand binding, a transmembrane domain for heterodimerization, and a cytoplasmic domain involved in signaling. ITGA4-mediated interactions are critical in the immune system, particularly in leukocyte trafficking and immune surveillance. Clinically, ITGA4 is implicated in inflammatory diseases such as multiple sclerosis, Crohn's disease, and asthma, with monoclonal antibodies targeting ITGA4 offering promising therapeutic approaches.