Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms (animals, plants and fungi).

In humans, the annexins are found inside the cell. However some annexins (Annexin A1, Annexin A2, and Annexin A5) can be secreted from the cytoplasm to outside cellular environments, such as blood.

Annexin is also known as lipocortin. Lipocortins suppress phospholipase A2. Increased expression of the gene coding for annexin-1 is one of the mechanisms by which glucocorticoids (such as cortisol) inhibit inflammation.

Introduction

The protein family of annexins has continued to grow since their association with intracellular membranes was first reported in 1977. The recognition that these proteins were members of a broad family first came from protein sequence comparisons and their cross-reactivity with antibodies. One of these workers (Geisow) coined the name Annexin shortly after.

As of 2002 160 annexin proteins have been identified in 65 different species. The criteria that a protein has to meet to be classified as an annexin are: it has to be capable of binding negatively charged phospholipids in a calcium dependent manner and must contain a 70 amino acid repeat sequence called an annexin repeat. Several proteins consist of annexin with other domains like gelsolin.

The basic structure of an annexin is composed of two major domains. The first is located at the COOH-terminal and is called the “core” region. The second is located at the NH2 terminal and is called the “head” region. The N terminal region is located on the concave side of the core region and is important for providing a binding site for cytoplasmic proteins. In some annexins it can become phosphorylated and can cause affinity changes for calcium in the core region or alter cytoplasmic protein interaction.

Annexins are important in various cellular and physiological processes such as providing a membrane scaffold, which is relevant to changes in the cell's shape. Also, annexins have been shown to be involved in trafficking and organization of vesicles, exocytosis, endocytosis and also calcium ion channel formation. Annexins have also been found outside the cell in the extracellular space and have been linked to fibrinolysis, coagulation, inflammation and apoptosis.

The first study to identify annexins was published by Creutz et al. (1978). These authors used bovine adrenal glands and identified a calcium dependent protein that was responsible for aggregation of granules amongst each other and the plasma membrane. This protein was given the name synexin, which comes from the Greek word “synexis” meaning “meeting”.

Structure

Several subfamilies of annexins have been identified based on structural and functional differences. However, all annexins share a common organizational theme that involves two distinct regions, an annexin core and an amino (N)-terminus. Each annexin core contains one type II, also known as an annexin type, calcium binding site; these binding sites are the typical location of ionic membrane interactions. They are located in some but not all of the membranous surfaces within a cell, which would be evidence of a heterogeneous distribution of Ca<sup>2+</sup> within the cell. During prophase, annexin XI will translocate to the nuclear envelope. The subject area has not been thoroughly studied, however it has been speculated that annexins may be involved in closing the neck of the matrix vesicle as it is endocytosed.

While different types of annexins can function as membrane scaffolds, annexin A-V is the most abundant membrane-bound annexin scaffold. Annexin A-V can form 2-dimensional networks when bound to the phosphatidylserine unit of the membrane. Annexin A-V is effective in stabilizing changes in cell shape during endocytosis and exocytosis, as well as other cell membrane processes. Alternatively, annexins A-I and A-II bind phosphatidylserine and phosphatidylcholine units in the cell membrane, and are often found forming monolayered clusters that lack a definite shape.

In addition, annexins A-I and A-II have been shown to bind PIP2 (phosphatidylinositol-4,5-bisphosphate) in the cell membrane and facilitate actin assembly near the membrane.

Membrane organization and trafficking

Several annexins have been shown to have active roles in the organization of the membrane. Annexin A-II has been extensively studied in this aspect of annexin function and is noted to be heavily involved in the organization of lipids in the bilayer near sites of actin cytoskeleton assembly. Annexin A-II can bind PIP2 in the cell membrane in vivo with a relatively high binding affinity.

In addition, Annexin A-II can bind other membrane lipids such as cholesterol, where this binding is made possible by the influx of calcium ions. The binding of Annexin A-II to lipids in the bilayer orchestrates the organization of lipid rafts in the bilayer at sites of actin assembly. In fact, annexin A-II is itself an actin-binding protein and therefore it can form a region of interaction with actin by means of its filamentous actin properties. In turn, this allows for further cell-cell interactions between monolayers of cells like epithelial and endothelial cells. In addition to annexin A-II, annexin A-XI has also been shown to organize cell membrane properties. Annexin A-XI is believed to be highly involved in the last stage of mitosis: cytokinesis. It is in this stage that daughter cells separate from one another because annexin A-XI inserts a new membrane that is believed to be required for abscission. Without annexin A-XI, it is believed that the daughter cells with not fully separate and may undergo apoptosis.

Clinical significance

Apoptosis and inflammation

Annexin A-I seems to be one of the most heavily involved annexins in anti-inflammatory responses. Upon infection or damage to tissues, annexin A-I is believed to reduce inflammation of tissues by interacting with annexin A-I receptors on leukocytes. In turn, the activation of these receptors functions to send the leukocytes to the site of infection and target the source of inflammation directly. As a result, this inhibits leukocyte (specifically neutrophils) extravasation and down regulates the magnitude of the inflammatory response. Without annexin A-I in mediating this response, neutrophil extravasation is highly active and worsens the inflammatory response in damaged or infected tissues.

Annexin A-I has also been implicated in apoptotic mechanisms in the cell. When expressed on the surface of neutrophils, annexin A-I promotes pro-apoptotic mechanisms. Alternatively, when expressed on the cell surface, annexin A-I promotes the removal of cells that have undergone apoptosis.

Moreover, annexin A-I has further medical implications in the treatment of cancer. Annexin A-I can be used as a cell surface protein to mark some forms of tumors that can be targeted by various immunotherapies with antibodies against annexin A-I.

Coagulation

Annexin A-V is the major player when it comes to mechanisms of coagulation. Like other annexin types, annexin A-V can also be expressed on the cell surface and can function to form 2-dimensional crystals to protect the lipids of the cell membrane from involvement in coagulation mechanisms.

Fibrinolysis

While several annexins may be involved in mechanisms of fibrinolysis, annexin A-II is the most prominent in mediating these responses. The expression of annexin A-II on the cell surface is believed to serve as a receptor for plasminogen, which functions to produce plasmin. Plasmin initiates fibrinolysis by degrading fibrin. The destruction of fibrin is a natural preventative measure because it prevents the formation of blood clots by fibrin networks.

Annexin A-II has medical implications because it can be utilized in treatments for various cardiovascular diseases that thrive on blood clotting through fibrin networks.

Types/subfamilies

  • Annexin, type I
  • Annexin, type II
  • Annexin, type III
  • Annexin, type IV
  • Annexin, type V
  • Annexin, type VI
  • Alpha giardin
  • Annexin, type X
  • Annexin, type VIII
  • Annexin, type XXXI
  • Annexin, type fungal XIV
  • Annexin, type plant
  • Annexin, type XIII
  • Annexin, type VII
  • Annexin like protein
  • Annexin XI

Human proteins containing this domain

ANXA1; ANXA10; ANXA11; ANXA13; ANXA2; ANXA3; ANXA4; ANXA5;

ANXA6; ANXA7; ANXA8; ANXA8L1; ANXA8L2; ANXA9;

References

Further reading

  • European Annexin Homepage, acquired on 20 August 2005
  • - Calculated spatial positions of annexins in membranes (the initially bound state)
  • Annexins repeated domain in PROSITE