Integrin

From Wikipedia, the free encyclopedia

An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. It plays a role in the attachment of a cell to the extracellular matrix (ECM) and to other cells, and in signal transduction from the ECM to the cell. There are many types of integrin, and many cells have multiple types on their surface. Integrins are of vital importance to all metazoans, from humans to sponges.

Other types of protein that play a role in cell-cell/cell-matrix interaction and communication are cadherins, CAMs and selectins.

1 Structure
- 1.1 High resolution structure
2 Function
- 2.1 Attachment of cell to the ECM
- 2.2 Signal transduction
3 Selected vertebrate integrins
4 Additional images
5 References
6 External links

[edit] Structure

Integrins are obligate heterodimers containing two distinct chains, called the α (alpha) and β (beta) subunits. About 18 α and 8 β subunits have been characterized:

Alpha: ITGA1 (CD49a), ITGA2 (CD49b), ITGA2B, ITGA3 (CD49c), ITGA4 (CD49d), ITGA5, ITGA6, ITGA7, ITGA8, ITGA9, ITGA10, ITGA11, ITGAD, ITGAE, ITGAL (CD11a), ITGAM (CD11b), ITGAV, ITGAW, ITGAX (CD11c)
Beta: ITGB1 (CD29), ITGB2 (CD18), ITGB3, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8

In addition, variants of some of the subunits are formed by differential splicing, for example 4 variants of the beta-1 subunit exist. Through different combinations of these alpha and beta subunits, some 24 unique integrins are generated ^[1]

Integrin subunits penetrate the plasma membrane, and in general have very short cytoplasmic domains of about 40-70 amino acids. 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 alpha and beta chains lie close together along a length of about 23 nm, the final 5 nm NH2-termini of each chain form a ligand-binding region for the ECM.

The molecular mass of the integrin subunits can vary from 90 Kda to 160 Kda. β subunits have four cysteine-rich repeated sequences. Both α and β subunits bind several divalent cations. The role of the α cations is unknown, but they may stabilize the folds of the protein. The β cations 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 NH2-terminal, the so called alpha-A domain (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 chain.

In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations 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 aminoacid code).

[edit] High resolution structure

Despites many years of effort, it was challenging to discover the high resolution structure of the integrins: membrane proteins are classically difficult to purify, and integrins are also large, complex, and linked to many sugar trees ("highly glycosylated"). Low resolution images of detergent extracts of intact integrin gpiibiiia, obtained using electron microscopy, and even data from indirect techniques, investigating 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 which 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 ^[2]. As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction with such sequences 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 which membrane proteins subtend to the plane of the membrane - it is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops - the evidence for this sweet supposition is noticeable by its absence. The integrin structure has drawn attention to this problem, which may have 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. And 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.

[edit] Function

Two main functions of integrins are:

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. These include: binding of viruses, including adenovirus, Echo viruses, Hanta viruses, foot and mouth disease viruses, to cells; immune patrolling. Cell migration.

A very prominent function of the integrins is seen in the molecule gpiibiiia, an integrin on the surface of blood platelets (thrombocytes)responsible for cross-linking platelets in fibrin within a developing blood clot. This switches its adhesiveness for fibrin/fibrinogen from being non-adhesive to being intensely sticky, in a fast and precisely controlled manner. As such it provides a thought-model for how many integrins are believed to be regulated. As you may have noted, although blood is normally very rich in platelets, we do not spontaneously clot. This is clearly good news. On the other side, and equally positively, even minor wounds are rapidly blocked by the mass of fibrin, platelets and erythrocytes in a blood clot. A primary event in clot formation is the binding of platelets to exposed collagen in the wound site, which leads to their "activation", and a clotting cascade. Among the many molecular events during activation, is the switching of gpiiaiib integrin from a quiescent state, unable to bind to fibrinogen/fibrin, to an active state, able to bind strongly to fibrinogen/fibrin. This is a remarkable event: first it involves all the gpiibiia on a single platelet (some 50000 molecules), second it is completed within 5 seconds, third, it increases the affinity of the integrin concerned over several orders of magnitude. Fourth, it involves wide spread changes in the molecular structure of the Gpiibiiia molecule, as reolved by LIBS antibodies, which gain the ability to bind gpiibiiia only following activation of the platelets. Finally, it is intensely locallized to the precise region of the damage, be it a couple of square microns, or the results of falling off a mountain bike at high speed.

[edit] Attachment of cell to the ECM

Integrins couple the ECM outside a cell to the cytoskeleton (in particular the microfilaments) inside the cell. Which ligand in the ECM the integrin can bind to is mainly decided by which α and β subunits the integrin is made of. Among the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. The connection between the cell and the ECM enables 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.

The connections between integrin and the ligands in the ECM and the microfilaments inside the cell are indirect: they are linked via scaffolding proteins like talin, paxillin and alpha-actinin. These act by regulating kinases like FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as Crk.

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, both literally and figuratively, of many cellular biological processes.

One of their most important functions is their role in cell migration. The movement of any body requires its feet to advance over the substratum. In this sense, integrins are the feet of the cell. Experimental evidence indicates that integrins can be released from attaching the cell to the substrate near the back of the cell. These released molecules are internalised by the cell by endocytosis and returned to the cell surface at the front of the cell by the endocytic cycle. In this way they are recycled for reuse.

[edit] Signal transduction

Integrins play an important role in cell signaling. Connection with ECM molecules can cause a signal to be relayed into the cell through protein kinases that are connected with the intracellular end of the integrin molecule.

The signals the cell receives through the integrin can have relation to:

[edit] Selected vertebrate integrins

The following are some of the integrins found in vertebrates.^[3]

Name	Distribution	Ligands
α1β1	Many	Collagens, laminins
α2β1	Many	Collagens, laminins
α4β1	Hematopoietic cells	Fibronectin, VCAM-1
α5β1	Fibroblasts	Fibronectin
αLβ2	T-lymphocytes	ICAM-1, ICAM-2
αMβ2	Monocytes	Serum proteins, ICAM-1
αIIbβ3	Platelets	Serum proteins, fibronectin
α6β4	Epithelial cells	Laminin

[edit] Additional images

Integrin (captions in German)

[edit] References

^ Hynes R (2002). "Integrins: bidirectional, allosteric signaling machines". Cell 110 (6): 673-87. PMID 12297042.
^ Smith J (2003). "Cilengitide Merck". Curr Opin Investig Drugs 4 (6): 741-5. PMID 12901235.
^ Molecular cell biology. Lodish, Harvey F. 5. ed. : - New York : W. H. Freeman and Co., 2003, 973 s. b ill. ISBN: 0-7167-4366-3