Annexin
Encyclopedia
Annexin is a common name for a group of cellular protein
s. They are found in all kingdoms (animal, plant and fungi) with the exception of the bacteria.
In humans, the annexins are found inside the cell
. However some annexins (Annexin A1, Annexin A2, and Annexin A5) have also been found outside the cellular environment, for example, in blood. How the annexins are transported out of the cell into the blood
is a mystery because they lack a signal peptide
necessary for proteins to be transported out of the cell.
Annexin is also known as lipocortin. Lipocortins suppress phospholipase A2
. This is the mechanism by which glucocorticoid
s (primarily cortisol
) inhibits inflammation
.
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 there has been 160 annexin proteins identified in 65 different species. The criteria that a protein has to meet to be classified as an annexin is: 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.
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 vesicle
s, 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”.
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
.
The diverse structure of the N-terminus confers specificity to annexin intracellular signaling. In all annexins the N-terminus is thought to sit inside the concave side of the annexin core and folds separately from the rest of the protein. The structure of this region can be divided into two broad categories, short and long N-termini. A short N-terminus, as seen in A-III, can consist of 16 or less amino acids and travels along the concave protein core interacting via hydrogen bonds. Short N-termini are thought to stabilize the annexin complex in order to increase calcium binding and can be the sites for post-translational modifications. Long N-termini can contain up to 40 residues and have a more complex role in annexin signaling. For example, in A-I the N-terminus folds into an amphipathic alpha-helix and inserts into the protein core, displacing helix D of annexin repeat III. However, when calcium binds, the N-terminus is pushed from the annexin core by conformational changes within the protein. Therefore, the N-terminus can interact with other proteins, notably the S-100 protein
family, and includes phosphorylation
sites which allow for further signaling. A-II can also use its long N-terminal to form a heterotrimer between a S100 protein and two peripheral annexins. The structural diversity of annexins is the grounds for the functional range of these complex, intracellular messengers.
activity has been shown to increase the concentrations of Annexins II,V within the nucleus. Annexin XI is predominantly located within the nucleus, and absent from the nucleoli. During prophase, annexin XI will translocate to the nuclear envelope.
pathway, specifically in the later stages, near or at the plasma membrane. Evidence of annexins or annexin-like proteins are involved in exocytosis has been found in lower organisms, such as the Paramecium
. Through antibody recognition, there is evidence of the annexin like proteins being involved in the positioning and attachment of secretory organelles in the organism Paramecium.
Annexin VII was the first annexin to be discovered while searching for proteins that promote the contact and fusion of chromaffin
granules. In Vitro studies however have shown that annexin VII does not promote the fusion of membranes, only the close attachment to one another.
) tyrosine kinase
which becomes phosphorylated on its N terminus when the receptor is internalized. Unique endosome
targeting sequences have been found in the N terminus of annexins I and II, which would be useful in sorting of endocytotic vesicles. Annexins are present in several different endocytotic processes. Annexin VI is thought to be involved in clathrin
coated budding events, while annexin II participates in both cholesteryl ester
internalization and the biogenesis of multi-vesicular endosomes.
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.
More recently, annexin scaffolding functions have been linked to medical applications. These medical implications have been uncovered with in vivo studies where the path of a fertilized egg is tracked to the uterus. After fertilization, the egg must enter a canal for which the opening is up to five times smaller than the diameter of the egg. Once the fertilized egg has passed through the opening, annexins are believed to promote membrane folding in an accordion-like fashion to return the stretched membrane back to its original form. Though this was discovered in the nematode
annexin NEX-1, it is believed that a similar mechanism takes place in humans and other mammals.
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
.
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.
. 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. Medically speaking, phospholipids can often be recruited in autoimmune responses, most commonly observed in cases of fetal loss during pregnancy. In such cases, antibodies against annexin A-V destroy its 2-dimensional crystal structure and uncover the phospholipids in the membrane, making them available for contribution to various coagulation mechanisms.
, 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
. The production of plasmin will counteract the fibrinolysis mechanism by promoting the degradation of fibrin
. In turn, the destruction of fibrin is a natural preventative measure because it prevents the formation of blood clots by fibrin networks.
Evidently, annexin A-II has medical implications because they can be utilized in treatments for various cardiovascular diseases that thrive on blood clotting through fibrin networks.
; ANXA13
; ANXA2; ANXA3; ANXA4
; ANXA5;
ANXA6
; ANXA7
; ANXA8; ANXA8L1; ANXA8L2
; ANXA9
;
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s. They are found in all kingdoms (animal, plant and fungi) with the exception of the bacteria.
In humans, the annexins are found inside the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. However some annexins (Annexin A1, Annexin A2, and Annexin A5) have also been found outside the cellular environment, for example, in blood. How the annexins are transported out of the cell into the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
is a mystery because they lack a signal peptide
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
necessary for proteins to be transported out of the cell.
Annexin is also known as lipocortin. Lipocortins suppress phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
. This is the mechanism by which glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s (primarily cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
) inhibits inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
.
Introduction
The proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
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 there has been 160 annexin proteins identified in 65 different species. The criteria that a protein has to meet to be classified as an annexin is: it has to be capable of binding negatively charged phospholipids in a calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
dependent manner and must contain a 70 amino acid repeat sequence called an annexin repeat.
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 vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
s, exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
, endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
and also calcium ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
formation. Annexins have also been found outside the cell in the extracellular space and have been linked to fibrinolysis
Fibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary fibrinolysis...
, coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
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
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
residue, upon calcium binding, which can interact with the hydrocarbon
Hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls....
chains of the lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
.
The diverse structure of the N-terminus confers specificity to annexin intracellular signaling. In all annexins the N-terminus is thought to sit inside the concave side of the annexin core and folds separately from the rest of the protein. The structure of this region can be divided into two broad categories, short and long N-termini. A short N-terminus, as seen in A-III, can consist of 16 or less amino acids and travels along the concave protein core interacting via hydrogen bonds. Short N-termini are thought to stabilize the annexin complex in order to increase calcium binding and can be the sites for post-translational modifications. Long N-termini can contain up to 40 residues and have a more complex role in annexin signaling. For example, in A-I the N-terminus folds into an amphipathic alpha-helix and inserts into the protein core, displacing helix D of annexin repeat III. However, when calcium binds, the N-terminus is pushed from the annexin core by conformational changes within the protein. Therefore, the N-terminus can interact with other proteins, notably the S-100 protein
S-100 protein
S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins...
family, and includes phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
sites which allow for further signaling. A-II can also use its long N-terminal to form a heterotrimer between a S100 protein and two peripheral annexins. The structural diversity of annexins is the grounds for the functional range of these complex, intracellular messengers.
Membrane
Annexins are characterized by their calcium dependent ability to bind to negatively charged phospholipids (i.e. membrane walls). They are located in some but not all of the membranous surfaces within a cell, which would be evidence of a heterogeneous distribution of Ca2+ within the cell.Nuclei
Annexin species (II,V,XI) have been found within the membranes. Tyrosine kinaseTyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
activity has been shown to increase the concentrations of Annexins II,V within the nucleus. Annexin XI is predominantly located within the nucleus, and absent from the nucleoli. During prophase, annexin XI will translocate to the nuclear envelope.
Bone
Annexins are abundant in bone matrix vesicles, and are speculated to play a role in Ca2+ entry into vesicles during hydroxyapatite formation. 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.Exocytosis
Annexins have been observed to play a role along the exocytoticExocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
pathway, specifically in the later stages, near or at the plasma membrane. Evidence of annexins or annexin-like proteins are involved in exocytosis has been found in lower organisms, such as the Paramecium
Paramecium
Paramecium is a group of unicellular ciliate protozoa, which are commonly studied as a representative of the ciliate group, and range from about 0.05 to 0.35 mm in length. Simple cilia cover the body, which allow the cell to move with a synchronous motion at speeds of approximately 12 body...
. Through antibody recognition, there is evidence of the annexin like proteins being involved in the positioning and attachment of secretory organelles in the organism Paramecium.
Annexin VII was the first annexin to be discovered while searching for proteins that promote the contact and fusion of chromaffin
Chromaffin
Taking up and staining strongly with Chromium salts.Chromaffin may refer to:*Chromaffin cells, neuroendocrine cells in the adrenal medulla.*Chromophil cells, hormone producing cells showing chromaffin granules that readily absorb chromium stains....
granules. In Vitro studies however have shown that annexin VII does not promote the fusion of membranes, only the close attachment to one another.
Endocytosis
Annexins have been found to be involved in the transport and also sorting of endocytotic events. Annexin one is a substrate of the EGF (epidermal growth factorEpidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
) tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
which becomes phosphorylated on its N terminus when the receptor is internalized. Unique endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...
targeting sequences have been found in the N terminus of annexins I and II, which would be useful in sorting of endocytotic vesicles. Annexins are present in several different endocytotic processes. Annexin VI is thought to be involved in clathrin
Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
coated budding events, while annexin II participates in both cholesteryl ester
Cholesteryl ester
A cholesteryl ester is, as its name would imply, an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl Esters have a lower solubility in water than Cholesterol and, in other words, are more hydrophobic...
internalization and the biogenesis of multi-vesicular endosomes.
Membrane scaffolding
Annexins can function as scaffolding proteins to anchor other proteins to the cell membrane. Annexins assemble as trimers, where this trimer formation is facilitated by calcium influx and efficient membrane binding. This trimer assembly is often stabilized by other membrane-bound annexin cores in the vicinity. Eventually, enough annexin trimers will assemble and bind the cell membrane. This will induce the formation of membrane-bound annexin networks. These networks can induce the indentation and vesicle budding during an exocytosis event.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
Phosphatidylserine
Phosphatidylserine is a phospholipid component, usually kept on the inner-leaflet of cell membranes by an enzyme called flippase...
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
Phosphatidylcholine
Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
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.
More recently, annexin scaffolding functions have been linked to medical applications. These medical implications have been uncovered with in vivo studies where the path of a fertilized egg is tracked to the uterus. After fertilization, the egg must enter a canal for which the opening is up to five times smaller than the diameter of the egg. Once the fertilized egg has passed through the opening, annexins are believed to promote membrane folding in an accordion-like fashion to return the stretched membrane back to its original form. Though this was discovered in the nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
annexin NEX-1, it is believed that a similar mechanism takes place in humans and other mammals.
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 cytoskeletonCytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic 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
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, 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
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
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
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
: cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...
. 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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Apoptosis and inflammation
Annexin A-I seems to be one of the most heavily involved annexins in anti-inflammatoryAnti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
responses. Upon infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
or damage to tissues, annexin A-I is believed to reduce inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
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
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Annexin A-I can be used as a cell surface protein to mark some forms of tumors that can be targeted by various immunotherapies
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
with antibodies against annexin A-I.
Coagulation
Annexin A-V is the major player when it comes to mechanisms of coagulationCoagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
. 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. Medically speaking, phospholipids can often be recruited in autoimmune responses, most commonly observed in cases of fetal loss during pregnancy. In such cases, antibodies against annexin A-V destroy its 2-dimensional crystal structure and uncover the phospholipids in the membrane, making them available for contribution to various coagulation mechanisms.
Fibrinolysis
While several annexins may be involved in mechanisms of fibrinolysisFibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary 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
Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...
. The production of plasmin will counteract the fibrinolysis mechanism by promoting the degradation of fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
. In turn, the destruction of fibrin is a natural preventative measure because it prevents the formation of blood clots by fibrin networks.
Evidently, annexin A-II has medical implications because they can be utilized in treatments for various cardiovascular diseases that thrive on blood clotting through fibrin networks.
Types/subfamilies
- Annexin, type IAnnexin A1Annexin A1 also known as lipocortin I is a protein that in humans is encoded by the ANXA1 gene.- Function :Annexin I belongs to the annexin family of Ca2+-dependent phospholipid-binding proteins that have a molecular weight of approximately 35,000 to 40,000 and are preferentially located on the...
- Annexin, type IIAnnexin A2Annexin A2 also known as annexin II is a protein that in humans is encoded by the ANXA2 gene.Annexin 2 is involved in diverse cellular processes such as cell motility , linkage of membrane-associated protein complexes to the actin cytoskeleton, endocytosis, fibrinolysis, ion channel formation, and...
- Annexin, type III
- Annexin, type IV
- Annexin, type VAnnexin A5Annexin A5 is a cellular protein in the annexin group. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of...
- 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; ANXA11ANXA11
Annexin A11 is a protein that in humans is encoded by the ANXA11 gene.-Interactions:ANXA11 has been shown to interact with PDCD6 and ALG2.-Further reading:...
; ANXA13
ANXA13
Annexin A13 is a protein that in humans is encoded by the ANXA13 gene.-Further reading:...
; ANXA2; ANXA3; ANXA4
ANXA4
Annexin A4 is a protein that in humans is encoded by the ANXA4 gene.-Further reading:...
; ANXA5;
ANXA6
ANXA6
Annexin A6 is a protein that in humans is encoded by the ANXA6 gene.-Interactions:ANXA6 has been shown to interact with RAS p21 protein activator 1.-Further reading:...
; ANXA7
ANXA7
Annexin A7 is a protein that in humans is encoded by the ANXA7 gene.-Interactions:ANXA7 has been shown to interact with ALG2 and SRI.-Further reading:...
; ANXA8; ANXA8L1; ANXA8L2
ANXA8L2
Annexin A8-like protein 2 is a protein that in humans is encoded by the ANXA8L2 gene.-Further reading:...
; ANXA9
ANXA9
Annexin A9 is a protein that in humans is encoded by the ANXA9 gene.-Further reading:...
;
External links
- European Annexin Homepage, acquired on 20 August 2005 - Calculated spatial positions of annexins in membranes (the initially bound state)
- Annexins repeated domain in PROSITEPROSITEPROSITE is a protein database. It consists of entries describing the protein families, domains and functional sites as well as amino acid patterns, signatures, and profiles in them. These are manually curated by a team of the Swiss Institute of Bioinformatics and tightly integrated into Swiss-Prot...