Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms (animal, plant 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 core region consists of an alpha helical disk. The convex side of this disk has type 2 calcium-binding sites. They are important for allowing interaction with the phospholipids at the plasma membrane. 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. The annexin core is highly conserved across the annexin family and the N-terminus varies greatly. The variability of the N-terminus is a physical construct for variation between subfamilies of annexins.
The 310 amino acid annexin core has four annexin repeats, each composed of 5 alpha-helices. The exception is annexin A-VI that has two annexin core domains connected by a flexible linker. A-VI was produced via duplication and fusion of the genes for A-V and A-X and therefore will not be discussed in length. The four annexin repeats produce a curved protein and allow functional differences based on the structure of the curve. The concave side of the annexin core interacts with the N-terminus and cytosolic second messengers, while the convex side of the annexin contains calcium binding sites. 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. However, other methods of membrane connections are possible. For example, A-V exposes a tryptophan residue, upon calcium binding, which can interact with the hydrocarbon chains of the lipid bilayer.