Talin is a high-molecular-weightcytoskeletal protein concentrated at regions of cell–substratum contact[1] and, inlymphocytes, at cell–cell contacts.[2][3] Discovered in 1983 byKeith Burridge and colleagues,[1] talin is a ubiquitouscytosolic protein that is found in high concentrations infocal adhesions. It is capable of linkingintegrins to theactin cytoskeleton either directly or indirectly by interacting withvinculin andα-actinin.[4]
Also, talin-1 drivesextravasation mechanism through engineered humanmicrovasculature in microfluidic systems. Talin-1 is involved in each part of extravasation affecting adhesion, trans-endothelial migration and the invasion stages.[5]
Integrin receptors are involved in the attachment of adherent cells to theextracellular matrix[6][7] and of lymphocytes to other cells. In these situations, talin codistributes with concentrations of integrins in theplasma membrane.[8][9] Furthermore,in vitro binding studies suggest that integrins bind to talin, although with low affinity.[10] Talin also binds with high affinity to vinculin,[11] another cytoskeletal protein concentrated at points ofcell adhesion.[12] Finally, talin is a substrate for the calcium-ion activatedprotease,calpain II,[13] which is also concentrated at points of cell–substratum contact.[14]
Talin is a mechanosensitive protein. Its mechanical vulnerability[15] and cellular position bridging integrin receptors and the actin cytoskeleton make it a fundamental protein inmechanotransduction. Mechanical stretching of talin promotes vinculin binding.[16]
Activation of the VBS leads to the recruitment of vinculin to form a complex with the integrins which aids stable cell adhesion. Formation of thecomplex between VBS and vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion'conformational change within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin tobind actin.[19]
Talin carries mechanical force (of 7-10 piconewton) during cell adhesion. It also allows cells to measure extracellular rigidity, since cells in which talin is prevented from forming mechanical linkages can no longer distinguish whether they are on a soft or rigid surface. The actin binding site2 is shown to be the major site for sensing the extracellular matrix rigidity.[22][23] Recently Kumaret al[24] combined cellularelectron cryo-tomography withFRET based tension measurements and find that the regions of high talin tension within focal adhesion have highly aligned and linear underlying filamentous actin structures while regions of low talin tension have less well-aligned actin filaments.
Vinculin binding sites areprotein domains predominantly found in talin and talin-like molecules, enabling binding of vinculin to talin, stabilising integrin-mediated cell-matrix junctions. Talin, in turn, links integrins to the actin cytoskeleton.
Theconsensus sequence for vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with asecondary structure prediction of fouramphipathic helices. The hydrophobicresidues that define the VBS are themselves 'masked' and are buried in the core of a series of helical bundles that make up the talin rod.[25]
A structure–function analysis reported in 2007[26] provides a cogent structural model (see top right) to explain talin-dependentintegrin activation in three steps:
The talin F3 domain (surface representation; colored by charge), freed from its autoinhibitory interactions in the full-length protein, becomes available for binding to the integrin.
F3 engages the membrane-distal part of theβ3-integrin tail (in red), which becomes ordered, but the α–β integrin interactions that hold the integrin in the low-affinity conformation remain intact.
In a subsequent step, F3 engages the membrane-proximal portion of the β3 tail while maintaining its membrane–distal interactions.
^Michelson AD (2006).Platelets, Second Edition. Boston: Academic Press.ISBN978-0-12-369367-9.
^Gilardi M, Bersini S, Calleja AB, Kamm RD, Vanoni M, Moretti M (April 2016). "PO-12 - The key role of talin-1 in cancer cell extravasation dissected through human vascularized 3D microfluidic model".Thrombosis Research.140 (Suppl 1): S180–1.doi:10.1016/S0049-3848(16)30145-1.PMID27161700.
^Geiger B (September 1979). "A 130K protein from chicken gizzard: its localization at the termini of microfilament bundles in cultured chicken cells".Cell.18 (1):193–205.doi:10.1016/0092-8674(79)90368-4.PMID574428.S2CID33153559.
^Beckerle MC, Burridge K, DeMartino GN, Croall DE (November 1987). "Colocalization of calcium-dependent protease II and one of its substrates at sites of cell adhesion".Cell.51 (4):569–77.doi:10.1016/0092-8674(87)90126-7.PMID2824061.S2CID25875416.
^Chishti AH, Kim AC, Marfatia SM, Lutchman M, Hanspal M, Jindal H, et al. (August 1998). "The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane".Trends in Biochemical Sciences.23 (8):281–2.doi:10.1016/S0968-0004(98)01237-7.PMID9757824.
^Gingras AR, Vogel KP, Steinhoff HJ, Ziegler WH, Patel B, Emsley J, Critchley DR, Roberts GC, Barsukov IL (February 2006). "Structural and dynamic characterization of a vinculin binding site in the talin rod".Biochemistry.45 (6):1805–17.doi:10.1021/bi052136l.PMID16460027.
