Annexins are a family of proteins found in various eukaryotic organisms, including mammals, plants, and birds. Present within cells, they participate in fundamental cellular activities. They associate with cellular membranes, contributing to cell integrity and communication.
The Structure and Mechanism of Annexins
Annexins have a distinctive structure with two main parts: a conserved C-terminal core domain and a variable N-terminal domain. The C-terminal core consists of four (or eight in Annexin A6) repeating segments, each about 70 amino acids long. These repeats form five alpha-helices, creating a bent disk-like shape where calcium and phospholipid binding sites are located.
The N-terminal domain varies significantly in length and sequence among different annexins. This variability allows each annexin type to interact with specific cellular partners and perform unique functions. Annexins function by binding to negatively charged phospholipids, such as phosphatidylserine, found on cell membranes. This binding requires calcium ions, which facilitate the annexin’s attachment to the membrane surface.
Key Functions in Cellular Processes
Annexins contribute to several cellular processes through their ability to interact with membranes. A significant role is membrane repair, where they act as a rapid response system to patch tears or damage. Annexins, including A1, A2, A4, A5, A6, and A11, are recruited to wound sites on the plasma membrane, helping to reseal the cell and prevent leakage.
Another important function is inflammation regulation, particularly involving Annexin A1. This protein limits inflammatory responses by inhibiting phospholipase A2 activity and reducing inflammatory precursors. Annexin A1 also influences the migration of immune cells, such as neutrophils, controlling their movement into inflamed tissues.
Annexins also participate in vesicle trafficking, the movement and fusion of small sacs called vesicles within the cell. For instance, Annexin A1 is involved in vesicle budding at late endosomes, while Annexin A2 helps regulate actin dynamics on endosomes and assists in their maturation. Annexins like A2 and A6 can also influence cholesterol transport between cellular compartments by regulating vesicle fusion.
Role in Health and Disease
Dysregulation of annexin function links to various health conditions. In autoimmune disorders, autoantibodies against several annexins are observed in patients with conditions like systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. Changes in annexin expression or function can contribute to these conditions. For example, Annexin A1 on early apoptotic cells can suppress immune responses, and its disruption might contribute to autoimmune issues.
Annexins are also implicated in the progression of various cancers. Their expression levels can be altered in different tumor types, influencing processes like cell growth, adhesion, and metastasis. For instance, Annexin A2 stimulates tumor cell proliferation and promotes cancer growth, also affecting tumor invasion and new blood vessel formation. Annexin A4 links to cell migration and invasion in various cancers, and Annexin A11 may play a part in hepatocellular carcinoma metastasis.
Annexin V as a Diagnostic Tool
Annexin V, also known as Annexin A5, is a widely used tool in scientific research and clinical diagnostics for detecting apoptosis, a process of programmed cell death. During early apoptosis, phosphatidylserine, normally on the inner cell membrane, moves to the outer surface. This externalization signals immune cells that the cell is undergoing programmed death.
Scientists use labeled Annexin V to identify apoptotic cells. Annexin V has a strong affinity for phosphatidylserine in the presence of calcium ions. When cells are stained with fluorescently tagged Annexin V, it binds to exposed phosphatidylserine on the surface of apoptotic cells. This binding allows researchers to visualize and quantify apoptotic cells, often using techniques like flow cytometry, where fluorescence intensity indicates phosphatidylserine exposure.