Editing Integrin (section)

== Structure ==
Integrins are obligate [[Heteromer|heterodimers]] composed of α and β [[Protein subunit|subunits]].  Several genes code for multiple [[Protein isoform|isoforms]] 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,<ref>{{cite book | title = Molecular Biology of the Cell | edition = 4th | year = 2002 | publisher = Garland Science | location = New York | chapter = Integrins | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK26867/ | vauthors = Bruce A, Johnson A, Lewis J, Raff M, Roberts K, Walter P }}</ref> in ''[[Drosophila]]'' five α and two β subunits, and in ''[[Caenorhabditis]]'' nematodes two α subunits and one β subunit.<ref name=hump>{{cite journal | vauthors = Humphries MJ | title = Integrin structure | journal = Biochemical Society Transactions | volume = 28 | issue = 4 | pages = 311–39 | year = 2000 | pmid = 10961914 | doi = 10.1042/0300-5127:0280311 }}</ref> The α and β subunits are both class I transmembrane proteins, so each penetrates the plasma membrane once, and can possess several [[cytoplasm]]ic domains.<ref name="pmid2977331">{{cite journal | vauthors = Nermut MV, Green NM, Eason P, Yamada SS, Yamada KM | title = Electron microscopy and structural model of human fibronectin receptor | journal = The EMBO Journal | volume = 7 | issue = 13 | pages = 4093–9 | date = December 1988 | pmid = 2977331 | pmc = 455118 | doi =  10.1002/j.1460-2075.1988.tb03303.x}}</ref>

{| class="wikitable" style="text-align:center; float:left; margin-right:1em;"
|+ alpha {{nobold|(mammal)}}
|-
! gene
! protein
! synonyms
|-
| {{gene|ITGA1}}
| [[CD49a]]
| VLA1
|-
| {{gene|ITGA2}}
| [[CD49b]]
| VLA2
|-
| {{gene|ITGA3}}
| [[CD49c]]
| VLA3
|-
| {{gene|ITGA4}}
| [[CD49d]]
| VLA4
|-
| {{gene|ITGA5}}
| [[CD49e]]
| VLA5
|-
| {{gene|ITGA6}}
| [[ITGA6|CD49f]]
| VLA6
|-
| {{gene|ITGA7}}
| [[ITGA7]]
| FLJ25220
|-
| {{gene|ITGA8}}
| [[ITGA8]]
|
|-
| {{gene|ITGA9}}
| [[ITGA9]]
| RLC
|-
| {{gene|ITGA10}}
| [[ITGA10]]
| PRO827
|-
| {{gene|ITGA11}}
| [[ITGA11]]
| HsT18964
|-
| {{gene|ITGAD}}
| [[ITGAD|CD11D]]
| FLJ39841
|-
| {{gene|ITGAE}}
| [[ITGAE|CD103]]
| HUMINAE
|-
| {{gene|ITGAL}}
| [[CD11a]]
| LFA1A
|-
| {{gene|ITGAM}}
| [[Integrin alpha M|CD11b]]
| MAC-1
|-
| {{gene|ITGAV}}
| [[ITGAV|CD51]]
| VNRA, MSK8
|-
| {{gene|ITGA2B}}
| [[ITGA2B|CD41]]
| GPIIb
|-
| {{gene|ITGAX}}
| [[CD11c]]
|
|}

{| class="wikitable" style="text-align:center; float:left; margin-right:1em;"
|+ beta {{nobold|(mammal)}}
|-
! gene
! protein
! synonyms
|-
| {{Gene|ITGB1}}
| [[CD29]]
| FNRB, MSK12, MDF2
|-
| {{Gene|ITGB2}}
| [[CD18]]
| LFA-1, MAC-1, MFI7
|-
| {{Gene|ITGB3}}
| [[CD61]]
| GP3A, GPIIIa
|-
| {{Gene|ITGB4}}
| [[ITGB4|CD104]]
|
|-
| {{Gene|ITGB5}}
| [[Integrin, beta 5|ITGB5]]
| FLJ26658
|-
| {{Gene|ITGB6}}
| [[Integrin, beta 6|ITGB6]]
|
|-
| {{Gene|ITGB7}}
| [[ITGB7]]
|
|-
| {{Gene|ITGB8}}
| [[ITGB8]]
|
|}{{clear left}}

Variants of some subunits are formed by differential [[RNA splicing]]; 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.<ref name="hynes1">{{cite journal | vauthors = Hynes RO | title = Integrins: bidirectional, allosteric signaling machines | journal = Cell | volume = 110 | issue = 6 | pages = 673–87 | date = September 2002 | pmid = 12297042 | doi = 10.1016/S0092-8674(02)00971-6 | s2cid = 30326350 | doi-access = free }}</ref>

Integrin subunits span the [[cell membrane]] 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&nbsp;[[nanometre|nm]]; the final 5&nbsp;nm [[N-terminus|N-termini]] of each chain forms a [[ligand (biochemistry)|ligand-binding]] region for the ECM. They have been compared to [[lobster]] 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]] of the integrin subunits can vary from 90&nbsp;[[atomic mass unit|kDa]] to 160&nbsp;kDa. Beta subunits have four [[cysteine]]-rich repeated sequences. Both α and β subunits bind several [[divalent]] [[cation]]s. The role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The [[Ion|cations]] in the β subunits are more interesting: they are directly involved in coordinating at least some of the [[ligand (biochemistry)|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 [[collagen]]s (e.g. integrins α1 β1, and α2 β1), or act as [[Cell–cell interaction|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&nbsp;mM (calcium) and 0.8&nbsp;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).

=== 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 [[glycosylation|glycosylated]] with many sugar 'trees' attached to them. 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.

The [[X-ray]] crystal structure obtained for the complete extracellular region of one integrin, αvβ3,<ref name="pmid11546839"/> 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]].<ref>{{cite journal | vauthors = Smith JW | title = Cilengitide Merck | journal = Current Opinion in Investigational Drugs | volume = 4 | issue = 6 | pages = 741–5 | date = June 2003 | pmid = 12901235 }}</ref> 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 [[orthogonality|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 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 [[antibody|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&nbsp;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 [[Extracellular matrix|ECM]]. In cells, the priming  is accomplished by a protein talin, which binds to the β tail of the integrin dimer and changes its conformation.<ref name="pmid15157154">{{cite journal | vauthors = Calderwood DA | title = Talin controls integrin activation | journal = Biochemical Society Transactions | volume = 32 | issue = Pt3 | pages = 434–7 | date = June 2004 | pmid = 15157154 | doi = 10.1042/BST0320434 }}</ref><ref name="pmid10497155">{{cite journal | vauthors = Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH | title = The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation | journal = The Journal of Biological Chemistry | volume = 274 | issue = 40 | pages = 28071–4 | date = October 1999 | pmid = 10497155 | doi = 10.1074/jbc.274.40.28071 | doi-access = free }}</ref> 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.<ref name="PMID20308986">{{cite journal | vauthors = Shattil SJ, Kim C, Ginsberg MH | title = The final steps of integrin activation: the end game | journal = Nature Reviews. Molecular Cell Biology | volume = 11 | issue = 4 | pages = 288–300 | date = April 2010 | pmid = 20308986 | pmc = 3929966 | doi = 10.1038/nrm2871 }}</ref> Moreover, talin proteins are able to dimerize<ref name="pmid8031639">{{cite journal | vauthors = Goldmann WH, Bremer A, Häner M, Aebi U, Isenberg G | title = Native talin is a dumbbell-shaped homodimer when it interacts with actin | journal = Journal of Structural Biology | volume = 112 | issue = 1 | pages = 3–10 | year = 1994 | pmid = 8031639 | doi = 10.1006/jsbi.1994.1002 }}</ref> 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.<ref name="pmid19240021">{{cite journal | vauthors = Harburger DS, Bouaouina M, Calderwood DA | title = Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects | journal = The Journal of Biological Chemistry | volume = 284 | issue = 17 | pages = 11485–97 | date = April 2009 | pmid = 19240021 | pmc = 2670154 | doi = 10.1074/jbc.M809233200 | doi-access = free }}</ref>