HOME

TheInfoList



OR:

Integrins are transmembrane receptors that facilitate cell-cell and cell-
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
(ECM) adhesion. Upon ligand binding, integrins activate
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
pathways that mediate cellular signals such as regulation of the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and sub ...
, organization of the intracellular
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is comp ...
, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface (''e.g''. signal
platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
s to initiate an interaction with
coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
factors). Several types of integrins exist, and one cell generally has multiple different types on its surface. Integrins are found in all animals while integrin-like receptors are found in plant cells. Integrins work alongside other proteins such as cadherins, the
immunoglobulin superfamily The immunoglobulin superfamily (IgSF) is a large protein superfamily 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 ...
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s, selectins and syndecans, to mediate cell–cell and cell–matrix interaction. Ligands for integrins include
fibronectin Fibronectin is a high-molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen ...
, vitronectin, collagen and
laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminin ...
.


Structure

Integrins are obligate heterodimers composed of α and β subunits. Several genes code for multiple
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
of these subunits, which gives rise to an array of unique integrins with varied activity. In mammals, integrins are assembled from eighteen α and eight β subunits, in ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many s ...
'' five α and two β subunits, and in '' Caenorhabditis'' nematodes two α subunits and one β subunit. The α and β subunits are both class I transmembrane proteins, so each penetrates the plasma membrane once, and can possess several
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
ic domains. Variants of some subunits are formed by differential
RNA splicing RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...
; for example, four variants of the beta-1 subunit exist. Through different combinations of the α and β subunits, 24 unique mammalian integrins are generated, excluding splice- and glycosylation variants. Integrin subunits span the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...
and have short cytoplasmic domains of 40–70 amino acids. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1,088 amino acids, one of the largest of any membrane protein. Outside the cell 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 ECM. They have been compared to
lobster Lobsters are a family (Nephropidae, synonym Homaridae) of marine crustaceans. They have long bodies with muscular tails and live in crevices or burrows on the sea floor. Three of their five pairs of legs have claws, including the first pair, ...
claws, although they don't actually "pinch" their ligand, they chemically interact with it at the insides of the "tips" of their "pinchers". The
molecular mass The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quant ...
of the integrin subunits can vary from 90  kDa to 160 kDa. Beta subunits have four
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, s ...
-rich repeated sequences. Both α and β subunits bind several divalent
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s. 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. Integrins can be categorized in multiple ways. For example, some α chains have 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 collagens (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 In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number 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 Arginylglycylaspartic acid (RGD) is the most common peptide motif responsible for cell adhesion to the extracellular matrix (ECM), found in species ranging from ''Drosophila'' to humans. Cell adhesion proteins called integrins recognize and bind ...
("RGD" in the one-letter amino acid code).


Structure

Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging, as membrane proteins are classically difficult to purify, and as integrins are large, complex and highly glycosylated with many sugar 'trees' attached to them. Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using
electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a ...
, 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. The
X-ray X-rays (or rarely, ''X-radiation'') are a form of high-energy electromagnetic radiation. In many languages, it is referred to as Röntgen radiation, after the German scientist Wilhelm Conrad Röntgen, who discovered it in 1895 and named it ' ...
crystal structure obtained for the complete extracellular region of one integrin, αvβ3, shows 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 In mathematics, orthogonality is the generalization of the geometric notion of ''perpendicularity''. By extension, orthogonality is also used to refer to the separation of specific features of a system. The term also has specialized meanings in ...
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 there is little evidence for this. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work. It appears that the integrin transmembrane helices are tilted (see "Activation" below), which hints that the extracellular chains may also not be orthogonal with respect to the membrane surface. 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 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 structural 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 ligand. Therefore, at least in biochemical experiments, integrin dimers must apparently not be 'unbent' in order to prime them and allow their binding to the
ECM ECM may refer to: Economics and commerce * Engineering change management * Equity capital markets * Error correction model, an econometric model * European Common Market Mathematics * Elliptic curve method * European Congress of Mathematics ...
. In cells, the priming is accomplished by a protein talin, which binds to the β tail of the integrin dimer and changes its conformation. The α and β integrin chains are both class-I transmembrane proteins: they pass the plasma membrane as single transmembrane alpha-helices. Unfortunately, the helices are too long, and recent studies suggest that, for integrin gpIIbIIIa, they are tilted with respect both to one another and to the plane of the membrane. Talin binding alters the angle of tilt of the β3 chain transmembrane helix in model systems and this may reflect a stage in the process of inside-out signalling which primes integrins. 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 In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting cell. More ...
. 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 cells to the ECM and signal transduction from the ECM to the cells. They are also involved in a wide range of other biological activities, including extravasation, cell-to-cell adhesion, cell migration, and as receptors for certain viruses, such as
adenovirus Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
, echovirus,
hantavirus ''Orthohantavirus'' is a genus of single-stranded, enveloped, negative-sense RNA viruses in the family '' Hantaviridae'' within the order '' Bunyavirales''. Members of this genus may be called orthohantaviruses or simply hantaviruses. Orthohan ...
, and
foot-and-mouth disease Foot-and-mouth disease (FMD) or hoof-and-mouth disease (HMD) is an infectious disease, infectious and sometimes fatal virus (biology), viral disease that affects cloven-hoofed animals, including domestic and wild Bovidae, bovids. The virus causes ...
, polio virus and other viruses. Recently, the importance of integrins in the progress of autoimmune disorders is also gaining attention of the scientists. These mechanoreceptors seem to regulate autoimmunity by dictating various intracellular pathways to control immune cell adhesion to endothelial cell layers followed by their trans-migration. This process might or might not be dependent on the sheer force faced by the extracellular parts of different integrins. A prominent function of the integrins is seen in the molecule GpIIb/IIIa, an integrin on the surface of blood
platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
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, GPIIb/IIIa 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 cell-
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
(ECM) outside a cell to the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is comp ...
(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 In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
s of integrins are
fibronectin Fibronectin is a high-molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collagen ...
, vitronectin, collagen, and
laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The 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 Ontogeny (also ontogenesis) is the origination and development of an organism (both physical and psychological, e.g., moral development), usually from the time of fertilization of the egg to adult. The term can also be used to refer to the stu ...
. 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 EGF may refer to: * E.G.F., a Gabonese company * East Grand Forks, Minnesota, a city * East Garforth railway station in England * Epidermal growth factor * Equity Group Foundation, a Kenyan charity * European Gendarmerie Force, a military unit of ...
, 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 is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...
complexes, which consist of integrins and many cytoplasmic proteins, such as talin, vinculin, paxillin, and alpha- actinin. These act by regulating
kinase In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
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 Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the ''CRK'' gene. The CRK protein participates in the Reelin signaling cascade downstream of DAB1. Function Adapter molecule crk is a member of ...
. 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 α6β4 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 signaling 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 is a biochemical tool used in the study of the rho-associated protein kinase (ROCK) signaling pathways. Y-27632 selectively inhibits p160ROCK, although it does inhibit other protein kinases such as PKCs at higher concentrations. It has be ...
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 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 dire ...
. Cells adhere to a
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...
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 is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
; 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. The cycle of integrin endocytosis and recycling back to the cell surface is important also for not migrating cells and during animal development.


Signal transduction

Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling. Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor. In a reverse direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor tyrosine kinases and their associated signaling molecules. The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signaling pathways regulating cell behavior. Clustering and activation of the integrins/actin complexes strengthen the focal adhesion interaction and initiate the framework for cell signaling through assembly of adhesomes. Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience: * cell growth *
cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...
* cell survival * cellular differentiation * apoptosis (programmed cell death) Knowledge of the relationship between integrins and receptor tyrosine kinase has laid a foundation for new approaches to cancer therapy. Specifically, targeting integrins associated with RTKs is an emerging approach for inhibiting angiogenesis.


Integrins and nerve repair

Integrins have an important function in neuroregeneration after injury of the
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain a ...
(PNS). Integrins are present at the growth cone of damaged PNS neurons and attach to ligands in the ECM to promote axon regeneration. It is unclear whether integrins can promote axon regeneration in the adult
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS). There are two obstacles that prevent integrin-mediated regeneration in the CNS: 1) integrins are not localised in the axon of most adult CNS neurons and 2) integrins become inactivated by molecules in the scar tissue after injury.


Vertebrate integrins

The following are 16 of the ~24 integrins found in vertebrates: Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which suggests 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.


See also

* D-dimer * Disintegrin *
Exopolymer An exopolymer is a biopolymer that is secreted by an organism into the environment (i.e. external to the organism). These exopolymers include the biofilms produced by bacteria to anchor them and protect them from environmental conditions. One type ...
*
Extracellular polymeric substance Extracellular polymeric substances (EPSs) are natural polymers of high molecular weight secreted by microorganisms into their environment. EPSs establish the functional and structural integrity of biofilms, and are considered the fundamental comp ...
(EPS or XPS)


References


External links


Talin substrate for calpain
– PMAP
The Proteolysis Map The Proteolysis MAP (PMAP) 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 PMAP was originally create ...
animation. * {{Signal transduction Transmembrane proteins Cell adhesion proteins