Talin (protein) explained

talin 1
Hgncid:11845
Symbol:TLN1
Altsymbols:TLN
Entrezgene:7094
Omim:186745
Refseq:NM_006289
Uniprot:Q9Y490
Chromosome:9
Arm:p
Band:23
Locussupplementarydata:-p21
talin 2
Hgncid:15447
Symbol:TLN2
Entrezgene:83660
Omim:607349
Refseq:NM_015059
Uniprot:Q9Y4G6
Chromosome:15
Arm:q
Band:15
Locussupplementarydata:-q21

Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact[1] and, in lymphocytes, at cell–cell contacts.[2] [3] Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions. It is capable of linking integrins to the actin cytoskeleton either directly or indirectly by interacting with vinculin and α-actinin.[4]

Also, talin-1 drives extravasation mechanism through engineered human microvasculature 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 the extracellular matrix[6] [7] and of lymphocytes to other cells. In these situations, talin codistributes with concentrations of integrins in the plasma 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 of cell adhesion.[12] Finally, talin is a substrate for the calcium-ion activated protease, 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 in mechanotransduction. Mechanical stretching of talin promotes vinculin binding.[16]

Protein domains

Talin consists of a large C-terminal rod domain that contains bundles of alpha helices and an N-terminal FERM (band 4.1, ezrin, radixin, and moesin) domain with three subdomains: F1, F2, and F3.[17] [18] [19] [20] The F3 subdomain of the FERM domain contains the highest affinity integrin-binding site for integrin β tails and is sufficient to activate integrins.[21]

Middle domain

Structure

Talin also has a middle domain, which has a structure consisting of five alpha helices that fold into a bundle. It contains a vinculin binding site (VBS) composed of a hydrophobic surface spanning five turns of helix four.

Function

Activation of the VBS leads to the recruitment of vinculin to form a complex with the integrins which aids stable cell adhesion. Formation of the complex 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 to bind actin.

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 Kumar et al [24] combined cellular electron cryo-tomography with FRET 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 site

Symbol:VBS
VBS
Pfam:PF08913
Interpro:IPR015009

Function

Vinculin binding sites are protein 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.

Structure

The consensus sequence for vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a secondary structure prediction of four amphipathic helices. The hydrophobic residues 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]

Activation of the integrin αIIbβ3

See also: integrin αIIbβ3. A structure–function analysis reported in 2007[26] provides a cogent structural model (see top right) to explain talin-dependent integrin activation in three steps:

  1. 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.
  2. F3 engages the membrane-distal part of the β3-integrin tail (in red), which becomes ordered, but the α–β integrin interactions that hold the integrin in the low-affinity conformation remain intact.
  3. In a subsequent step, F3 engages the membrane-proximal portion of the β3 tail while maintaining its membrane–distal interactions.

Human proteins containing this domain

TLN1

TLN2;

See also

External links

Notes and References

  1. Burridge K, Connell L . A new protein of adhesion plaques and ruffling membranes . The Journal of Cell Biology . 97 . 2 . 359–67 . August 1983 . 6684120 . 2112532 . 10.1083/jcb.97.2.359 .
  2. Kupfer A, Singer SJ, Dennert G . On the mechanism of unidirectional killing in mixtures of two cytotoxic T lymphocytes. Unidirectional polarization of cytoplasmic organelles and the membrane-associated cytoskeleton in the effector cell . The Journal of Experimental Medicine . 163 . 3 . 489–98 . March 1986 . 3081676 . 2188060 . 10.1084/jem.163.3.489 .
  3. Burn P, Kupfer A, Singer SJ . Dynamic membrane-cytoskeletal interactions: specific association of integrin and talin arises in vivo after phorbol ester treatment of peripheral blood lymphocytes . Proceedings of the National Academy of Sciences of the United States of America . 85 . 2 . 497–501 . January 1988 . 3124107 . 279577 . 10.1073/pnas.85.2.497 . 1988PNAS...85..497B . free .
  4. Book: Michelson, Alan D. . Platelets, Second Edition . Academic Press . Boston . 2006 . 978-0-12-369367-9 .
  5. Gilardi M, Bersini S, Calleja AB, Kamm RD, Vanoni M, Moretti M . 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 . April 2016 . 27161700 . 10.1016/S0049-3848(16)30145-1 .
  6. Hynes RO . Integrins: a family of cell surface receptors . Cell . 48 . 4 . 549–54 . February 1987 . 3028640 . 10.1016/0092-8674(87)90233-9 . 27274629 .
  7. Ruoslahti E, Pierschbacher MD . New perspectives in cell adhesion: RGD and integrins . Science . 238 . 4826 . 491–7 . October 1987 . 2821619 . 10.1126/science.2821619 . 1987Sci...238..491R .
  8. Chen WT, Hasegawa E, Hasegawa T, Weinstock C, Yamada KM . Development of cell surface linkage complexes in cultured fibroblasts . The Journal of Cell Biology . 100 . 4 . 1103–14 . April 1985 . 3884631 . 2113771 . 10.1083/jcb.100.4.1103 .
  9. Kupfer A, Singer SJ . The specific interaction of helper T cells and antigen-presenting B cells. IV. Membrane and cytoskeletal reorganizations in the bound T cell as a function of antigen dose . The Journal of Experimental Medicine . 170 . 5 . 1697–713 . November 1989 . 2530300 . 2189515 . 10.1084/jem.170.5.1697 .
  10. Horwitz A, Duggan K, Buck C, Beckerle MC, Burridge K . Interaction of plasma membrane fibronectin receptor with talin--a transmembrane linkage . Nature . 320 . 6062 . 531–3 . 1986 . 2938015 . 10.1038/320531a0 . 1986Natur.320..531H . 4356748 .
  11. Burridge K, Mangeat P . An interaction between vinculin and talin . Nature . 308 . 5961 . 744–6 . 1984 . 6425696 . 10.1038/308744a0 . 1984Natur.308..744B . 4316613 .
  12. Geiger B . A 130K protein from chicken gizzard: its localization at the termini of microfilament bundles in cultured chicken cells . Cell . 18 . 1 . 193–205 . September 1979 . 574428 . 10.1016/0092-8674(79)90368-4 . 33153559 .
  13. Fox JE, Goll DE, Reynolds CC, Phillips DR . Identification of two proteins (actin-binding protein and P235) that are hydrolyzed by endogenous Ca2+-dependent protease during platelet aggregation . The Journal of Biological Chemistry . 260 . 2 . 1060–6 . January 1985 . 10.1016/S0021-9258(20)71208-1 . 2981831 . free .
  14. Beckerle MC, Burridge K, DeMartino GN, Croall DE . Colocalization of calcium-dependent protease II and one of its substrates at sites of cell adhesion . Cell . 51 . 4 . 569–77 . November 1987 . 2824061 . 10.1016/0092-8674(87)90126-7 . 25875416 .
  15. Haining AW, von Essen M, Attwood SJ, Hytönen VP, Del Río Hernández A . All Subdomains of the Talin Rod Are Mechanically Vulnerable and May Contribute To Cellular Mechanosensing . ACS Nano . 10 . 7 . 6648–58 . July 2016 . 27380548 . 4982699 . 10.1021/acsnano.6b01658 .
  16. del Rio A, Perez-Jimenez R, Liu R, Roca-Cusachs P, Fernandez JM, Sheetz MP . Stretching single talin rod molecules activates vinculin binding . Science . 323 . 5914 . 638–41 . January 2009 . 19179532 . 10.1126/science.1162912 . 9339221 . 2009Sci...323..638D . 206514978 .
  17. Chishti AH, Kim AC, Marfatia SM, Lutchman M, Hanspal M, Jindal H, Liu SC, Low PS, Rouleau GA, Mohandas N, Chasis JA, Conboy JG, Gascard P, Takakuwa Y, Huang SC, Benz EJ, Bretscher A, Fehon RG, Gusella JF, Ramesh V, Solomon F, Marchesi VT, Tsukita S, Tsukita S, Hoover KB . 6 . The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane . Trends in Biochemical Sciences . 23 . 8 . 281–2 . August 1998 . 9757824 . 10.1016/S0968-0004(98)01237-7 .
  18. García-Alvarez B, de Pereda JM, Calderwood DA, Ulmer TS, Critchley D, Campbell ID, Ginsberg MH, Liddington RC . Structural determinants of integrin recognition by talin . Molecular Cell . 11 . 1 . 49–58 . January 2003 . 12535520 . 10.1016/S1097-2765(02)00823-7 . free .
  19. Papagrigoriou E, Gingras AR, Barsukov IL, Bate N, Fillingham IJ, Patel B, Frank R, Ziegler WH, Roberts GC, Critchley DR, Emsley J . 6 . Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle . The EMBO Journal . 23 . 15 . 2942–51 . August 2004 . 15272303 . 514914 . 10.1038/sj.emboj.7600285 .
  20. Rees DJ, Ades SE, Singer SJ, Hynes RO . Sequence and domain structure of talin . Nature . 347 . 6294 . 685–9 . October 1990 . 2120593 . 10.1038/347685a0 . 1990Natur.347..685R . 4274654 .
  21. Calderwood DA, Yan B, de Pereda JM, Alvarez BG, Fujioka Y, Liddington RC, Ginsberg MH . The phosphotyrosine binding-like domain of talin activates integrins . The Journal of Biological Chemistry . 277 . 24 . 21749–58 . June 2002 . 11932255 . 10.1074/jbc.M111996200 . free .
  22. Austen K, Ringer P, Mehlich A, Chrostek-Grashoff A, Kluger C, Klingner C, Sabass B, Zent R, Rief M, Grashoff C . Extracellular rigidity sensing by talin isoform-specific mechanical linkages . Nature Cell Biology . 17 . 12 . 1597–606 . December 2015 . 26523364 . 4662888 . 10.1038/ncb3268 .
  23. Kumar A, Ouyang M, Van den Dries K, McGhee EJ, Tanaka K, Anderson MD, Groisman A, Goult BT, Anderson KI, Schwartz MA . 6 . Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity . The Journal of Cell Biology . 213 . 3 . 371–83 . May 2016 . 27161398 . 4862330 . 10.1083/jcb.201510012 .
  24. Kumar A, Anderson KL, Swift MF, Hanein D, Volkmann N, Schwartz MA . Local Tension on Talin in Focal Adhesions Correlates with F-Actin Alignment at the Nanometer Scale . Biophysical Journal . 115 . 8 . 1569–1579 . September 2018 . 30274833 . 6372196 . 10.1016/j.bpj.2018.08.045. 2018BpJ...115.1569K .
  25. Gingras AR, Vogel KP, Steinhoff HJ, Ziegler WH, Patel B, Emsley J, Critchley DR, Roberts GC, Barsukov IL . Structural and dynamic characterization of a vinculin binding site in the talin rod . Biochemistry . 45 . 6 . 1805–17 . February 2006 . 16460027 . 10.1021/bi052136l .
  26. Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH, Campbell ID . Structural basis of integrin activation by talin . Cell . 128 . 1 . 171–82 . January 2007 . 17218263 . 10.1016/j.cell.2006.10.048 . 18307182 . free .

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