Integrin
Encyclopedia
Integrins are receptors
that mediate attachment between a cell
and the tissues surrounding it, which may be other cells or the ECM
. They also play a role in cell signaling
and thereby regulate cellular shape, motility, and the cell cycle
.
Typically, receptors inform a cell of the molecules in its environment and the cell responds. Not only do integrins perform this outside-in signalling, but they also operate an inside-out mode. Thus, they transduce
information from the ECM to the cell as well as reveal the status of the cell to the outside, allowing rapid and flexible responses to changes in the environment, for example to allow blood coagulation
by platelets.
There are many types of integrin, and many cells have multiple types on their surface. Integrins are of vital importance to all animal
s and have been found in all animals investigated, from sponges to mammal
s. Integrins have been extensively studied in humans.
Integrins work alongside other protein
s such as cadherin
s, Immunoglobulin superfamily
cell adhesion molecule
s, selectin
s and syndecan
s to mediate cell–cell and cell–matrix interaction and communication. Integrins bind cell surface and ECM components such as fibronectin
, vitronectin
, collagen
, and laminin
.
heterodimers containing two distinct chains, called the α (alpha) and β (beta) subunits. In mammal
s, eighteen α and eight β subunits have been characterized, whereas the Drosophila
genome
encodes only five α and two β subunits, and Caenorhabditis
nematodes possess genes for two α subunits and one β. The α and β subunits each contain two separate tails, both of which penetrate the plasma membrane and possess small cytoplasmic domains.
alpha
beta
In addition, variants of some of the subunits are formed by differential splicing; for example four variants of the beta-1 subunit exist. Through different combinations of these α and β subunits, some 24 unique integrins are generated, although the number varies according to different studies.
Integrin subunits span the plasma membrane and in general have very short cytoplasmic domains of about 40–70 amino acid
s. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1088 amino acids, one of the largest known cytoplasmic domains of any membrane protein. Outside the cell plasma membrane, the α and β chains lie close together along a length of about 23 nm
; the final 5 nm N-termini of each chain forms a ligand-binding
region for the extracellular matrix
(ECM).
The molecular mass
of the integrin subunits can vary from 90 kDa
to 160 kDa. Beta subunits have four cysteine
-rich repeated sequences. Both α and β subunits bind several divalent
cations. The role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The cations in the β subunits are more interesting: they are directly involved in coordinating at least some of the ligands
that integrins bind.
There are various ways of categorizing the integrins. For example, a subset of the α chains has an additional structural element (or "domain") inserted toward the N-terminal, the alpha-A domain (so called because it has a similar structure to the A-domains found in the protein von Willebrand factor
; it is also termed the α-I domain). Integrins carrying this domain either bind to collagen
s (e.g. integrins α1 β1, and α2 β1), or act as cell
-cell adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding site, but this A-domain is found on the β subunit.
In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentration
s of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM (calcium) and 0.8 mM (magnesium). The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine
-Glycine
-Aspartic acid
("RGD" in the one-letter amino acid code).
"). Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, and even data from indirect techniques that investigate the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular models postulated for the rest of the chains.
Despite these wide-ranging efforts, the X-ray
crystal structure obtained for the complete extracellular region of one integrin, αvβ3, was a surprise. It showed the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide
. As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour.
The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally
from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops, but the evidence for this sweet supposition is noticeable by its absence. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work.
Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is that integrin function involves changes in shape to move the ligand-binding site into a more accessible position, away from the cell surface, and this shape change also triggers intracellular signaling. There is a wide body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of antibodies
that only recognize integrins when they have bound to their ligands, or are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how the changes detected with antibodies look like on the structure is still unknown.
. In cells, the priming is accomplished by a protein named Talin
, which binds to the β tail of the integrin dimer and changes its conformation. Moreover, talin proteins are able to dimerize and thus are thought to intervene in the clustering of integrin dimers which leads to the formation of a focal adhesion
. Recently, the Kindlin-1 and Kindlin-2 proteins have also been found to interact with integrin and activate it.
However, they are also involved in a wide range of other biological activities, including immune patrolling, cell migration, and binding to cells by certain viruses, such as adenovirus, echovirus
, hantavirus
, and foot and mouth disease viruses.
A prominent function of the integrins is seen in the molecule GPIIbIIIa
, an integrin on the surface of blood platelet
s (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIbIIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.
(in particular the microfilaments) inside the cell. Which ligand in the ECM the integrin can bind to is defined by which α and β subunits the integrin is made of. Among the ligand
s of integrins are fibronectin
, vitronectin
, collagen
, and laminin
. The connection between the cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in ontogeny
.
Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF
, EGF
, and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart of many cellular biological processes. The attachment of the cell takes place through formation of cell adhesion
complexes, which consist of integrins and many cytoplasmic proteins such as talin, vinculin
, paxillin
, and alpha-actinin
. These act by regulating kinase
s such as FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as CRK
. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin alpha6beta4 is an exception: it links to the keratin intermediate filament system in epithelial cells.
Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering. The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signalling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy. As previously stated, these complexes connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5 nm and spaced at approximately 45 nm. Treatment with Rho-kinase inhibitor Y-27632
reduces the size of the particle, and it is extremely mechanosensitive.
One important function of integrins on cells in tissue culture is their role in cell migration
. Cells adhere to a substrate
through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by endocytosis
; they are transported through the cell to its front by the endocytic cycle
where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front. It is not yet clear whether cell migration in tissue culture is an artefact of integrin processing, or whether such integrin dependent cell migration also occurs in living organisms.
s that are indirectly and temporarily connected with the intracellular end of the integrin molecule, likely following shape changes directly stimulated by ECM binding.
The signals the cell receives through the integrin can have relation to:
Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which proves that during embryonal development, one integrin may substitute its function for another in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand binding, which then activates the receptors—also by inducing a shape change—to trigger outside-in signal transduction.
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
that mediate attachment between a 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....
and the tissues surrounding it, which may be other cells or the ECM
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
. They also play a role in cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
and thereby regulate cellular shape, motility, and the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
.
Typically, receptors inform a cell of the molecules in its environment and the cell responds. Not only do integrins perform this outside-in signalling, but they also operate an inside-out mode. Thus, they transduce
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
information from the ECM to the cell as well as reveal the status of the cell to the outside, allowing rapid and flexible responses to changes in the environment, for example to allow blood 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...
by platelets.
There are many types of integrin, and many cells have multiple types on their surface. Integrins are of vital importance to all animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s and have been found in all animals investigated, from sponges to mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s. Integrins have been extensively studied in humans.
Integrins work alongside other protein
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 such as cadherin
Cadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
s, Immunoglobulin superfamily
Immunoglobulin superfamily
The immunoglobulin superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins ; they all possess a...
cell adhesion molecule
Cell adhesion molecule
Cell Adhesion Molecules are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix in the process called cell adhesion....
s, selectin
Selectin
Selectins are a family of cell adhesion molecules . All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding...
s and syndecan
Syndecan
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains, which allow for interaction with a large variety of ligands including...
s to mediate cell–cell and cell–matrix interaction and communication. Integrins bind cell surface and ECM components such as fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, vitronectin
Vitronectin
Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family...
, collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, and laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
.
Structure
Integrins are obligateObligate
Obligate means "by necessity" and is used mainly in biology in phrases such as:* Obligate aerobe, an organism that cannot survive without oxygen* Obligate anaerobe, an organism that cannot survive in the presence of oxygen...
heterodimers containing two distinct chains, called the α (alpha) and β (beta) subunits. In mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, eighteen α and eight β subunits have been characterized, whereas the Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
encodes only five α and two β subunits, and Caenorhabditis
Caenorhabditis
Caenorhabditis is a genus of nematodes which live in bacteria-rich environments like compost piles and decaying dead animals. It contains the noted model organism Caenorhabditis elegans and several other species for which a genome sequence is either available or currently being determined. The two...
nematodes possess genes for two α subunits and one β. The α and β subunits each contain two separate tails, both of which penetrate the plasma membrane and possess small cytoplasmic domains.
alpha
| gene | protein | synonyms are |
|---|---|---|
| CD49a CD49a CD49a is an integrin alpha subunit. It makes up half of the α1β1 integrin duplex.-Further reading:-External links:* Info with links in the... |
VLA1 | |
| CD49b CD49b CD49b is a protein which in humans is encoded by the CD49b gene.The CD49b protein is an integrin alpha subunit. It makes up half of the α2β1 integrin duplex. Integrins are heterodimeric integral membrane glycoproteins composed of a distinct alpha chain and a common beta chain... |
VLA2 | |
| CD49c CD49c Integrin alpha-3 is a protein that in humans is encoded by the ITGA3 gene.ITGA3 is an integrin alpha subunit. Together with beta-1 subunit, it makes up half of the α3β1 integrin duplex that plays a role in neural migration and corticogenesis, acted upon by such factors as netrin-1 and reelin.ITGA3... |
VLA3 | |
| CD49d CD49d CD49d is an integrin alpha subunit. It makes up half of the α4β1 lymphocyte homing receptor.-Interactions:CD49d has been shown to interact with LGALS8 and Paxillin.-External links:* Info with links in the... |
VLA4 | |
| CD49e | VLA5 | |
| CD49f ITGA6 Integrin alpha-6 is a protein that in humans is encoded by the ITGA6 gene.-Interactions:ITGA6 has been shown to interact with TSPAN4 and GIPC1.-External links:* Info with links in the... |
VLA6 | |
| ITGA7 ITGA7 Integrin alpha-7 is a protein that in humans is encoded by the ITGA7 gene.-Interactions:ITGA7 has been shown to interact with FHL2 and FHL3.-External links:* Info with links in the... |
FLJ25220 | |
| ITGA8 ITGA8 Integrin alpha-8 is a protein that in humans is encoded by the ITGA8 gene.-External links:* Info with links in the... |
||
| ITGA9 ITGA9 Integrin alpha-9 is a protein that in humans is encoded by the ITGA9 gene.-External links:* Info with links in the... |
RLC | |
| ITGA10 ITGA10 Integrin alpha-10 also known as ITGA10 is a protein that in humans is encoded by the ITGA10 gene.-Function:Integrins are integral membrane proteins composed of an alpha chain and a beta chain, and are known to participate in cell adhesion as well as cell-surface mediated signalling... |
||
| ITGA11 ITGA11 Integrin alpha-11 is a protein that in humans is encoded by the ITGA11 gene.This gene encodes an alpha integrin. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This protein contains an I domain, is expressed in muscle tissue, dimerizes with beta... |
HsT18964 | |
| CD11D ITGAD Integrin alpha-D is a protein that in humans is encoded by the ITGAD gene.-External links:* Info with links in the... |
FLJ39841 | |
| CD103 ITGAE Integrin, alpha E also known as CD103 is an integrin protein that in human is encoded by the ITGAE gene. CD103 binds integrin beta 7 to form the complete heterodimeric integrin molecule αEβ7, which has no distinct name... |
HUMINAE | |
| CD11a CD11a Integrin, alpha L , also known as ITGAL, is a human gene which functions in the immune system. It is involved in cellular adhesion and costimulatory signaling... |
LFA1A | |
| CD11b Integrin alpha M Integrin alpha M is one protein subunit that forms the heterodimeric integrin alpha-M beta-2 molecule, also known as macrophage-1 antigen or complement receptor 3 . ITGAM is also known as CR3A, and cluster of differentiation molecule 11B... |
MAC-1 | |
| CD51 ITGAV Integrin alpha-V is a protein that in humans is encoded by the ITGAV gene.-Further reading:-External links:* Info with links in the... |
VNRA, MSK8 | |
| ITGAW | ||
| CD11c CD11c CD11c, also known as Integrin, alpha X , is a human gene.CD11c is a type I transmembrane protein found at high levels on most human dendritic cells, but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst;... |
beta
| gene | protein | synonyms |
|---|---|---|
| CD29 CD29 Integrin beta-1 is a protein that in humans is encoded by the ITGB1 gene. CD29 is an integrin unit associated with very late antigen receptors. It is known to conjoin with alpha-3 subunit to create α3β1 complex that reacts to such molecules as netrin-1 and reelin.Integrins are heterodimeric... |
FNRB, MSK12, MDF2 | |
| CD18 CD18 Integrin beta-2 is a protein that in humans is encoded by the ITGB2 gene.It is the beta subunit of four different structures:* LFA-1 * Macrophage-1 antigen * Integrin alphaXbeta2... |
LFA-1, MAC-1, MFI7 | |
| CD61 CD61 Integrin beta-3 or CD61 is a protein that in humans is encoded by the ITGB3 gene. CD61 is a cluster of differentiation found on thrombocytes.-Structure and function:... |
GP3A, GPIIIa | |
| CD104 ITGB4 Integrin, beta 4 also known as CD104 , is a human gene.-Interactions:ITGB4 has been shown to interact with Collagen, type XVII, alpha 1, EIF6 and Erbin.-Further reading:... |
||
| ITGB5 Integrin, beta 5 Integrin beta-5 is a protein that in humans is encoded by the ITGB5 gene.-Interactions:Integrin, beta 5 has been shown to interact with PTK2, Annexin A5 and PAK4.-External links:* Info with links in the... |
FLJ26658 | |
| ITGB6 Integrin, beta 6 Integrin beta-6 is a protein that in humans is encoded by the ITGB6 gene.-Interactions:Integrin, beta 6 has been shown to interact with FHL2.-External links:* * Info with links in the... |
||
| ITGB7 ITGB7 Integrin beta-7 is a protein that in humans is encoded by the ITGB7 gene.-External links:* Info with links in the... |
||
| ITGB8 ITGB8 Integrin beta-8 is a protein that in humans is encoded by the ITGB8 gene.- Function :This gene is a member of the integrin beta chain family and encodes a single-pass type I membrane protein with a VWFA domain and four cysteine-rich repeats. This protein noncovalently binds to an alpha subunit to... |
In addition, variants of some of the subunits are formed by differential splicing; for example four variants of the beta-1 subunit exist. Through different combinations of these α and β subunits, some 24 unique integrins are generated, although the number varies according to different studies.
Integrin subunits span the plasma membrane and in general have very short cytoplasmic domains of about 40–70 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1088 amino acids, one of the largest known cytoplasmic domains of any membrane protein. Outside the cell plasma membrane, the α and β chains lie close together along a length of about 23 nm
Nanometre
A nanometre is a unit of length in the metric system, equal to one billionth of a metre. The name combines the SI prefix nano- with the parent unit name metre .The nanometre is often used to express dimensions on the atomic scale: the diameter...
; the final 5 nm N-termini of each chain forms a ligand-binding
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
region for the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM).
The molecular mass
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...
of the integrin subunits can vary from 90 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
to 160 kDa. Beta subunits have four cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
-rich repeated sequences. Both α and β subunits bind several divalent
Divalent
In chemistry, a divalent ion or molecule has a valence of two and thus can form two bonds with other ions or molecules. An older term for divalent is bivalent....
cations. The role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The cations in the β subunits are more interesting: they are directly involved in coordinating at least some of the ligands
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
that integrins bind.
There are various ways of categorizing the integrins. For example, a subset of the α chains has an additional structural element (or "domain") inserted toward the N-terminal, the alpha-A domain (so called because it has a similar structure to the A-domains found in the protein von Willebrand factor
Von Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
; it is also termed the α-I domain). Integrins carrying this domain either bind to collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
s (e.g. integrins α1 β1, and α2 β1), or act as 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....
-cell adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding site, but this A-domain is found on the β subunit.
In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM (calcium) and 0.8 mM (magnesium). The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-Glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-Aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
("RGD" in the one-letter amino acid code).
High resolution structure
Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging: membrane proteins are classically difficult to purify, and integrins are also large, complex and linked to many sugar trees ("highly glycosylatedGlycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
"). Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, and even data from indirect techniques that investigate the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular models postulated for the rest of the chains.
Despite these wide-ranging efforts, the X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
crystal structure obtained for the complete extracellular region of one integrin, αvβ3, was a surprise. It showed the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide
Cilengitide
Cilengitide is a molecule designed and synthesized at the Technical University Munich in collaboration with Merck KGaA in Darmstadt. It is based on the cyclic peptide cyclo, which is selective for αv integrins, which are important in angiogenesis...
. As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour.
The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally
Orthogonality
Orthogonality occurs when two things can vary independently, they are uncorrelated, or they are perpendicular.-Mathematics:In mathematics, two vectors are orthogonal if they are perpendicular, i.e., they form a right angle...
from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops, but the evidence for this sweet supposition is noticeable by its absence. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work.
Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is that integrin function involves changes in shape to move the ligand-binding site into a more accessible position, away from the cell surface, and this shape change also triggers intracellular signaling. There is a wide body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
that only recognize integrins when they have bound to their ligands, or are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how the changes detected with antibodies look like on the structure is still unknown.
Activation
When released into the cell membrane, newly synthesized integrin dimers are speculated to be found in the same "bent" conformation revealed by the strucutral studies described above. One school of thought claims that this bent form prevents them from interacting with their ligands, although bent forms can predominate in high-resolution EM structures of integrin bound to an ECM ligands. Therefore, at least in biochemical experiments, integrin dimers must apparently not be 'unbent' in order to prime them and allow their binding to the ECMExtracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
. In cells, the priming is accomplished by a protein named Talin
Talin
Talin is a town in the Aragatsotn province of Armenia. It has a population of 5,371. The seventh century Talin Cathedral is located in the town.- History :...
, which binds to the β tail of the integrin dimer and changes its conformation. Moreover, talin proteins are able to dimerize and thus are thought to intervene in the clustering of integrin dimers which leads to the formation of a focal adhesion
Focal adhesion
In cell biology, focal adhesions are specific types of large macromolecular assemblies through which both mechanical force and regulatory signals are transmitted. More precisely, they can be considered as sub-cellular macromolecules that mediate the regulatory effects In cell biology, focal...
. Recently, the Kindlin-1 and Kindlin-2 proteins have also been found to interact with integrin and activate it.
Function
Integrins have two main functions:- Attachment of the cell to the ECM
- Signal transduction from the ECM to the cell
However, they are also involved in a wide range of other biological activities, including immune patrolling, cell migration, and binding to cells by certain viruses, such as adenovirus, echovirus
Echovirus
An ECHO virus, is a type of RNA virus that belongs to the genus Enterovirus of the Picornaviridae family...
, hantavirus
Hantavirus
Hantaviruses are negative sense RNA viruses in the Bunyaviridae family. Humans may be infected with hantaviruses through rodent bites, urine, saliva or contact with rodent waste products...
, and foot and mouth disease viruses.
A prominent function of the integrins is seen in the molecule GPIIbIIIa
Glycoprotein IIb/IIIa
In medicine, glycoprotein IIb/IIIa is an integrin complex found on platelets. It is a receptor for fibrinogen and aids in platelet activation. The complex is formed via calcium-dependent association of gpIIb and gpIIIa, a required step in normal platelet aggregation and endothelial adherence...
, an integrin on the surface of blood platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIbIIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.
Attachment of cell to the ECM
Integrins couple the ECM outside a cell to the 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...
(in particular the microfilaments) inside the cell. Which ligand in the ECM the integrin can bind to is defined by which α and β subunits the integrin is made of. Among the ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s of integrins are fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, vitronectin
Vitronectin
Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family...
, collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, and laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
. The connection between the cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in ontogeny
Ontogeny
Ontogeny is the origin and the development of an organism – for example: from the fertilized egg to mature form. It covers in essence, the study of an organism's lifespan...
.
Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
, EGF
Epidermal 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...
, and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart of many cellular biological processes. The attachment of the cell takes place through formation of cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
complexes, which consist of integrins and many cytoplasmic proteins such as talin, vinculin
Vinculin
In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton...
, paxillin
Paxillin
Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge and should not be confused with the neurotoxin paxilline. The C-terminal region of paxillin contains four LIM domains that target paxillin to focal adhesions, it is presumed through a direct...
, and alpha-actinin
Actinin
Actinin is a microfilament protein. α-Actinin is necessary for the attachment of actin filaments to the Z-lines in skeletal muscle cells, and to the dense bodies in smooth muscle cells...
. These act by regulating kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s such as FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as CRK
CRK (gene)
Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin alpha6beta4 is an exception: it links to the keratin intermediate filament system in epithelial cells.
Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering. The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signalling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy. As previously stated, these complexes connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5 nm and spaced at approximately 45 nm. Treatment with Rho-kinase inhibitor Y-27632
Y-27632
Y-27632 is a biochemical tool used in the study of the rho-associated protein kinase signaling pathways. Y-27632 selectively inhibits p160ROCK....
reduces the size of the particle, and it is extremely mechanosensitive.
One important function of integrins on cells in tissue culture is their role in cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
. Cells adhere to a substrate
Substrate (biology)
In biology a substrate is the surface a plant or animal lives upon and grows on. A substrate can include biotic or abiotic materials and animals. For example, encrusting algae that lives on a rock can be substrate for another animal that lives on top of the algae. See also substrate .-External...
through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by 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...
; they are transported through the cell to its front by the endocytic cycle
Endocytic cycle
Most animal cells take up portions of their surface plasma membranes in a process called endocytosis. The main route of endocytosis is the coated pit, which buds into a cell to form a cytoplasmic vesicle — a clathrin-coated vesicle. The membrane so internalised is processed in a series of...
where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front. It is not yet clear whether cell migration in tissue culture is an artefact of integrin processing, or whether such integrin dependent cell migration also occurs in living organisms.
Signal transduction
Integrins play an important role in cell signalling. Connection with ECM molecules can cause a signal to be relayed into the cell through protein kinaseKinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s that are indirectly and temporarily connected with the intracellular end of the integrin molecule, likely following shape changes directly stimulated by ECM binding.
The signals the cell receives through the integrin can have relation to:
- cell growthCell growthThe term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, - cell divisionCell divisionCell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, - cell survival,
- cellular differentiationCellular differentiationIn developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, and - apoptosis (programmed cell death)ApoptosisApoptosis 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...
.
Vertebrate integrins
The following are some of the integrins found in vertebrates:| Name | Synonyms | Distribution | Ligands >- | α1β1 |
Many | Collagen Collagen Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content... s, laminin Laminin Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs... s >- | α2β1 |
Many | >- | VLA-4 | Hematopoietic cells | Fibronectin Fibronectin Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans... , VCAM-1 VCAM-1 Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 or cluster of differentiation 106 is a protein that in humans is encoded by the VCAM1 gene... >- | α5β1 Alpha-5 beta-1 α5β1 is an integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis. It is composed of α5 and β1 subunits. It is the primary receptor for fibronectin... |
fibronectin receptor | widespread | >- | laminin receptor | widespread | >- | LFA-1 | T-lymphocytes | ICAM-1 ICAM-1 ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system... , ICAM-2 >- | αMβ2 Integrin alpha M Integrin alpha M is one protein subunit that forms the heterodimeric integrin alpha-M beta-2 molecule, also known as macrophage-1 antigen or complement receptor 3 . ITGAM is also known as CR3A, and cluster of differentiation molecule 11B... |
Mac-1, CR3 | Neutrophils and monocyte Monocyte Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function... s |
Serum Blood plasma Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid... proteins, ICAM-1 >- | αIIbβ3 |
Platelet Platelet Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days... s |
>- | vitronectin receptor | activated endothelial cells, melanoma, glioblastoma | vitronectin Vitronectin Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family... , fibronectin, fibrinogen, osteopontin Osteopontin Osteopontin , also known as bone sialoprotein I , early T-lymphocyte activation , secreted phosphoprotein 1 , 2ar and Rickettsia resistance , is a human gene product, which is also conserved in other species... , Cyr61 >- | αVβ5 Alpha-v beta-5 αVβ5 is a type of integrin that binds to matrix macromolecules and proteinases and thereby stimulates angiogenesis. However, recent studies indicate that it actually inhibits angiogenesis.... |
widespread, esp. fibroblasts, epithelial cells | vitronectin Vitronectin Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family... and adenovirus >- | alpha-v beta-6|αVβ6 |
proliferating epithelia, esp. lung and liver | fibronectin Fibronectin Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans... ; TGFβ1+3 >- | α6β4 |
Epithelial cells | Laminin Laminin Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs... |
Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which proves that during embryonal development, one integrin may substitute its function for another in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand binding, which then activates the receptors—also by inducing a shape change—to trigger outside-in signal transduction.
External links
- The Integrin Protein
- Talin substrate for calpain – PMAP The Proteolysis MapThe Proteolysis MapThe Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...
animation.