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Annexin A5 (ANXA5) is a calcium phospholipid binding protein composed of a single chain of 319 amino acid polypeptides, and its function is mainly derived from the special structure of ANXA5.
The ability of ANXA5 to participate in important functions inside and outside the cell is mainly due to its acidic phospholipids. The acid phospholipid of ANXA5 is located in a highly conserved core composed of four identical regions, in which the protein core is folded into a 5α helix and then inverted into a right-hand supercoil. And these four areas are packaged into a micro-convex surface of the disc-like structure, which is where the Ca2+ and phospholipids are cyclically bonded. The reverse side is a concave surface, which is mainly formed by the extension of the N-amino end of each region to form a C-helix and closes the structure with the collection region I and the region IV. This end is called the C-end. The opposite end is the N-amino terminus, which is composed of fewer residues compared to other Ca2+-dependent phospholipid-binding proteins. It is also because of the different order and length of amino acid arrangements, which form their respective characteristics.
ANXA5 and Tumor
ANXA5 has a diametrically opposite mechanism of action in different tumors. Evidence that promotes tumor progression suggests that up-regulation of ANXA5 activates multidrug resistance-associated protein (MRP) and promotes drug resistance in gastric cancer. And ANXA5 is positively correlated with tumor stage of cancers such as colon cancer and breast cancer. Evidence for tumor suppression suggests that ANXA5 directly inhibits PKC expression while reducing the effects of Shc and Grb2. It also reduces the expression of vimentin (Vim) to reduce its response to actin gamma 1, ACTG1 and promote tumor cell apoptosis.
At the same time, ANXA5 adhesion to PS can promote T cell-mediated tumor immune response and improve tumor-free survival. Jeong et al. found that ANXA5 also has the opposite effect in the same organ tumor, that is, ANXA5 promotes apoptosis of colon cancer cells, but at the same time, it is highly expressed in advanced colon cancer tissues. Peng et al. believe that this may be the role of ANXA5 in inflammatory carcinogenesis, that is, ANXA5 mediates apoptosis of cancer cells and promotes the immune response.
Figure 1. Roles of Anxa5 playing in tumors. (Ota, et al. 2013).
ANXA5 and Obstetric Diseases
Thrombosis tends to be one of the important causes of recurrent miscarriage. The hemodynamic balance during pregnancy is determined by the occupancy of phosphatidylserine (PS) and its cohesiveness to stimulate tandem coagulation factors. ANXA5 is the only Ca2+-dependent phospholipid-binding protein that can form a two-dimensional crystal bonded to the PS surface, which can form lateral aggregates on the cell membrane to stimulate the defense function of ANXA5 on the placental villi, thereby exerting its anticoagulant function.
In addition, ANXA5 is significantly reduced before convulsions in pregnant women, and inversely proportional to proteinuria, edema, and blood clots. It is speculated that it may be because the decrease of ANXA5 leads to the activation of tandem coagulation in the chorionic space and the production of prothrombin, thereby increasing the placental vascular resistance, tissue hypoxia and placental damage. But further principles have not yet been elucidated.
ANXA5 and Immune Diseases
Exposure to PS is a signal of the process of condensation and apoptosis. Extracellular ANXA5 recognizes the signal and binds to PS, forming an anti-clotting barrier to block the availability of phospholipid-dependent coagulants for anionic phospholipids and prevent the formation of lupus-related thrombi. However, ANXA5 is a phospholipid cofactor that is mistaken for the formation of phospholipid-protein complexes and thus targets anti-phospholipid antibody attacks. In addition, Wahezi et al. found that antiphospholipid antibodies bind β2 glycoprotein I (β2GPI) to have a higher affinity for phospholipids. Therefore it is able to compete with ANXA5 for the ability to bind phospholipids, thereby reducing its anticoagulant effect.
However, the opposite view suggests that ANXA5 is not significantly associated with thrombosis and that they have separate systems. Moreover, ANXA5 acts as a Ca2+ occupant outside the cell, and its prolongation of plasma thrombin is due to a decrease in available Ca2+. But this may not show the actual termination of the coagulation process of this transformation, but the formation of artificial cockroaches, and among different races, ANXA5 has a different correlation with the thrombus.
ANXA5 and Cardiovascular Disease
Domeij et al. found that ANXA5 inhibits the pro-inflammatory response of lysophosphatidylcholine (LPC) and reduces the increase of oxidized low-density lipoprotein (LDL) and leukocyte adhesion. ANXA5 reduces foam cell formation by directly acting on macrophages, reducing its uptake of LDL cholesterol, to maintain vascular plaque stability and prevent thrombosis.
ANXA5 blocks the release of endothelial particles and the adhesion of platelets and leukocytes by adhering to the PS of activated cells in the damaged segment. Then it affects the level of systemic inflammatory response and cytokine circulation, while reducing the unfolded protein response caused by endoplasmic reticulum stress and improving local and systemic vascular endothelial anti-inflammatory function. In addition, ANXA5 reflects the systemic and subventricular function of the ventricles and the process of cardiac remodeling, but the mechanism is still unknown.