ITGA2B - integrin subunit alpha 2b |Elisa - Clia - Antibody - Protein

Background

ITGA2B, also known as integrin alpha 2b or CD41, is a transmembrane glycoprotein that plays a central role in platelet adhesion and aggregation. It is primarily expressed on platelets and megakaryocytes. Together with integrin beta 3 (ITGB3), ITGA2B forms the αIIbβ3 integrin complex (also known as GPIIb/IIIa), which is the most abundant integrin on the surface of platelets and is crucial for blood clot formation (hemostasis). This receptor mediates platelet aggregation by binding to fibrinogen, von Willebrand factor (vWF), fibronectin, and other adhesive proteins during platelet activation. When platelets are stimulated, the αIIbβ3 complex undergoes a conformational change that allows it to bind its ligands and mediate platelet-platelet interactions.

Mutations in ITGA2B can lead to Glanzmann thrombasthenia (GT), a rare inherited bleeding disorder characterized by defective platelet aggregation. This highlights the importance of αIIbβ3 integrin in normal platelet function and hemostasis.

Protein Structure

The ITGA2B protein is a transmembrane glycoprotein composed of approximately 1039 amino acids. Like other integrins, it has a multi-domain structure, which includes an extracellular domain, a transmembrane domain, and a cytoplasmic tail. The ITGA2B gene is located on chromosome 17q21.32 and encodes for this critical subunit that pairs with ITGB3 to form the αIIbβ3 integrin complex.

Extracellular Domain:

• The extracellular region of ITGA2B consists of multiple domains essential for ligand binding and integrin activation. It contains a seven-bladed beta-propeller domain, which is a characteristic feature of integrin alpha subunits. This region is responsible for interacting with ligands such as fibrinogen, vWF, and other adhesive molecules during platelet aggregation.
• Calcium-binding sites: The extracellular domain contains several calcium-binding motifs, which are important for maintaining the stability and conformation of the integrin. Calcium ions play a role in the structural integrity of the integrin and are critical for ligand binding.
• In association with ITGB3, the ligand-binding headpiece is formed, which undergoes conformational changes from a bent, inactive state to an extended, active state during platelet activation. This conformational change allows for high-affinity ligand binding and the formation of platelet aggregates.

Transmembrane Domain:

• ITGA2B contains a single-pass transmembrane domain composed of a hydrophobic stretch of amino acids. This region spans the plasma membrane and facilitates the integrin's connection with the intracellular environment.
• The transmembrane domain of ITGA2B interacts closely with the transmembrane region of ITGB3. These interactions are critical for integrin activation, as changes in the positioning of the transmembrane domains help propagate conformational changes from the extracellular domain to the cytoplasmic tail.

Cytoplasmic Domain:

• The cytoplasmic tail of ITGA2B is relatively short and lacks enzymatic activity. However, it plays an important role in transmitting signals between the extracellular matrix and the intracellular environment, a process known as "inside-out signaling" and "outside-in signaling".
• During platelet activation, intracellular signals cause the cytoplasmic tails of ITGA2B and ITGB3 to separate, promoting integrin activation and ligand binding. Conversely, ligand binding to the extracellular domain of αIIbβ3 triggers intracellular signaling cascades through the cytoplasmic domain, which are essential for platelet spreading, clot retraction, and stable thrombus formation.

Classification and Subtypes

ITGA2B is part of the integrin family, a large group of cell surface receptors that mediate cell-cell and cell-extracellular matrix (ECM) interactions. Integrins are heterodimers consisting of alpha (α) and beta (β) subunits. ITGA2B belongs to the α integrin subfamily and specifically pairs with ITGB3 to form the αIIbβ3 complex.

There are no subtypes of ITGA2B itself; however, its functional activity is defined by its heterodimerization with ITGB3. The αIIbβ3 integrin (GPIIb/IIIa) is a unique receptor on platelets that specifically binds fibrinogen and is crucial for hemostasis. While ITGA2B and ITGB3 are distinct molecules, their function as a complex is what defines their biological role in platelet aggregation.

Function and Biological Significance

The primary biological role of ITGA2B is in hemostasis, where it mediates platelet adhesion, activation, and aggregation—key steps in the formation of a blood clot. In its inactive state, the αIIbβ3 integrin adopts a bent conformation that prevents ligand binding. Upon platelet activation by agonists such as thrombin, ADP, or collagen, αIIbβ3 undergoes a conformational change to an extended, high-affinity state, allowing it to bind fibrinogen and vWF.

Platelet Aggregation:

• Once activated, the αIIbβ3 integrin binds fibrinogen, which acts as a bridge between adjacent platelets. This binding is crucial for platelet aggregation and the formation of a primary hemostatic plug at sites of vascular injury. The αIIbβ3-fibrinogen interaction is also essential for stabilizing platelet-platelet contacts, which is critical for thrombus formation.

Hemostasis:

• In addition to platelet aggregation, αIIbβ3 plays a role in other processes of primary hemostasis, such as platelet spreading and clot retraction. After platelets aggregate, they undergo further shape changes, spreading across the injured vessel surface. This allows for better coverage of the damaged area and helps stop bleeding. In later stages, outside-in signaling via αIIbβ3 induces clot retraction, a process that tightens the clot and helps wound healing.

Cell Signaling:

• The αIIbβ3 integrin is involved in transmitting signals from the extracellular environment to the intracellular space, a process known as outside-in signaling. This signaling pathway contributes to cytoskeletal rearrangements, which are essential for platelet spreading, stable clot formation, and clot retraction.

Angiogenesis and Wound Healing:

• Beyond its role in hemostasis, the αIIbβ3 integrin has also been implicated in angiogenesis and wound healing. It can interact with the extracellular matrix proteins, facilitating endothelial cell migration and promoting the formation of new blood vessels.

Clinical Issues

Mutations or deficiencies in ITGA2B can lead to Glanzmann thrombasthenia (GT), a rare autosomal recessive bleeding disorder characterized by defective platelet aggregation. Individuals with GT lack functional αIIbβ3 integrin, leading to impaired platelet adhesion and severe bleeding tendencies. The clinical features of Glanzmann thrombasthenia include spontaneous mucocutaneous bleeding, prolonged bleeding after injury, and abnormal clot retraction.

Glanzmann Thrombasthenia (GT):

• Patients with GT often experience prolonged bleeding times and difficulty forming stable clots. Diagnosis is typically made by flow cytometry, which shows a lack of αIIbβ3 expression or function. Treatment may include platelet transfusions for acute bleeding episodes or surgical procedures. In some cases, recombinant activated factor VII (rFVIIa) has been used as a treatment for bleeding in these patients.

Thrombosis and Cardiovascular Diseases:

• While deficiencies in ITGA2B result in bleeding disorders, overactivation of αIIbβ3 can contribute to thrombotic conditions, such as myocardial infarction or stroke. In these cases, excessive platelet aggregation leads to the formation of abnormal blood clots in the arteries. As a result, αIIbβ3 is a target for antiplatelet therapies, such as GPIIb/IIIa inhibitors (e.g., abciximab, tirofiban), which are used to prevent thrombosis in patients undergoing percutaneous coronary interventions (PCI) or those at high risk for acute coronary syndrome (ACS).

Cancer:

• The role of αIIbβ3 integrin in angiogenesis and cell migration has also drawn attention in the context of cancer. Studies have suggested that αIIbβ3 may facilitate tumor cell adhesion to the vascular endothelium, promoting tumor metastasis. Inhibitors of αIIbβ3 are being investigated for their potential to prevent metastatic dissemination in certain cancers.

Summary

ITGA2B, the integrin subunit alpha 2b, is a critical component of the αIIbβ3 integrin complex, primarily expressed on platelets and megakaryocytes. This integrin plays an essential role in hemostasis by mediating platelet adhesion, activation, and aggregation at sites of vascular injury. Its multi-domain structure enables it to undergo conformational changes necessary for ligand binding and platelet aggregation, while its cytoplasmic domain facilitates crucial signaling pathways for clot retraction and stabilization.

Dysfunction or deficiency of ITGA2B leads to Glanzmann thrombasthenia, a bleeding disorder characterized by impaired platelet aggregation. Conversely, overactivation of αIIbβ3 can contribute to thrombotic events, making it a target for antiplatelet therapies. Furthermore, its role in angiogenesis, wound healing, and potentially cancer metastasis underscores its broader biological significance. The study of ITGA2B and its associated clinical conditions continues to offer insights into the regulation of platelet function and the development of targeted therapies for both bleeding and thrombotic disorders.