Talin (protein)

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,[1] 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]

Talin, middle domain
Identifiers
SymbolTalin_middle
PfamPF09141
InterProIPR015224
SCOP21sj7 / SCOPe / SUPFAM
talin 1
Identifiers
SymbolTLN1
Alt. symbolsTLN
NCBI gene7094
HGNC11845
OMIM186745
RefSeqNM_006289
UniProtQ9Y490
Other data
LocusChr. 9 p23-p21
talin 2
Identifiers
SymbolTLN2
NCBI gene83660
HGNC15447
OMIM607349
RefSeqNM_015059
UniProtQ9Y4G6
Other data
LocusChr. 15 q15-q21

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]

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.[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 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
VBS
human vinculin head (1-258) in complex with talin's vinculin binding site 3 (residues 1944-1969)
Identifiers
SymbolVBS
PfamPF08913
InterProIPR015009

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
Model of talin-induced integrin activation

A structure–function analysis reported recently[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

References
  1. Burridge K, Connell L (August 1983). "A new protein of adhesion plaques and ruffling membranes". The Journal of Cell Biology. 97 (2): 359–67. doi:10.1083/jcb.97.2.359. PMC 2112532. PMID 6684120.
  2. Kupfer A, Singer SJ, Dennert G (March 1986). "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. doi:10.1084/jem.163.3.489. PMC 2188060. PMID 3081676.
  3. Burn P, Kupfer A, Singer SJ (January 1988). "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. Bibcode:1988PNAS...85..497B. doi:10.1073/pnas.85.2.497. PMC 279577. PMID 3124107.
  4. Michelson AD (2006). Platelets, Second Edition. Boston: Academic Press. ISBN 978-0-12-369367-9.
  5. 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. PMID 27161700.
  6. Hynes RO (February 1987). "Integrins: a family of cell surface receptors". Cell. 48 (4): 549–54. doi:10.1016/0092-8674(87)90233-9. PMID 3028640. S2CID 27274629.
  7. Ruoslahti E, Pierschbacher MD (October 1987). "New perspectives in cell adhesion: RGD and integrins". Science. 238 (4826): 491–7. Bibcode:1987Sci...238..491R. doi:10.1126/science.2821619. PMID 2821619.
  8. Chen WT, Hasegawa E, Hasegawa T, Weinstock C, Yamada KM (April 1985). "Development of cell surface linkage complexes in cultured fibroblasts". The Journal of Cell Biology. 100 (4): 1103–14. doi:10.1083/jcb.100.4.1103. PMC 2113771. PMID 3884631.
  9. Kupfer A, Singer SJ (November 1989). "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. doi:10.1084/jem.170.5.1697. PMC 2189515. PMID 2530300.
  10. Horwitz A, Duggan K, Buck C, Beckerle MC, Burridge K (1986). "Interaction of plasma membrane fibronectin receptor with talin--a transmembrane linkage". Nature. 320 (6062): 531–3. Bibcode:1986Natur.320..531H. doi:10.1038/320531a0. PMID 2938015. S2CID 4356748.
  11. Burridge K, Mangeat P (1984). "An interaction between vinculin and talin". Nature. 308 (5961): 744–6. Bibcode:1984Natur.308..744B. doi:10.1038/308744a0. PMID 6425696. S2CID 4316613.
  12. 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. PMID 574428. S2CID 33153559.
  13. Fox JE, Goll DE, Reynolds CC, Phillips DR (January 1985). "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. doi:10.1016/S0021-9258(20)71208-1. PMID 2981831.
  14. 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. PMID 2824061. S2CID 25875416.
  15. Haining AW, von Essen M, Attwood SJ, Hytönen VP, Del Río Hernández A (July 2016). "All Subdomains of the Talin Rod Are Mechanically Vulnerable and May Contribute To Cellular Mechanosensing". ACS Nano. 10 (7): 6648–58. doi:10.1021/acsnano.6b01658. PMC 4982699. PMID 27380548.
  16. del Rio A, Perez-Jimenez R, Liu R, Roca-Cusachs P, Fernandez JM, Sheetz MP (January 2009). "Stretching single talin rod molecules activates vinculin binding". Science. 323 (5914): 638–41. Bibcode:2009Sci...323..638D. doi:10.1126/science.1162912. PMID 19179532. S2CID 206514978.
  17. 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. PMID 9757824.
  18. García-Alvarez B, de Pereda JM, Calderwood DA, Ulmer TS, Critchley D, Campbell ID, Ginsberg MH, Liddington RC (January 2003). "Structural determinants of integrin recognition by talin". Molecular Cell. 11 (1): 49–58. doi:10.1016/S1097-2765(02)00823-7. PMID 12535520.
  19. Papagrigoriou E, Gingras AR, Barsukov IL, Bate N, Fillingham IJ, Patel B, et al. (August 2004). "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle". The EMBO Journal. 23 (15): 2942–51. doi:10.1038/sj.emboj.7600285. PMC 514914. PMID 15272303.
  20. Rees DJ, Ades SE, Singer SJ, Hynes RO (October 1990). "Sequence and domain structure of talin". Nature. 347 (6294): 685–9. Bibcode:1990Natur.347..685R. doi:10.1038/347685a0. PMID 2120593. S2CID 4274654.
  21. Calderwood DA, Yan B, de Pereda JM, Alvarez BG, Fujioka Y, Liddington RC, Ginsberg MH (June 2002). "The phosphotyrosine binding-like domain of talin activates integrins". The Journal of Biological Chemistry. 277 (24): 21749–58. doi:10.1074/jbc.M111996200. PMID 11932255.
  22. Austen K, Ringer P, Mehlich A, Chrostek-Grashoff A, Kluger C, Klingner C, Sabass B, Zent R, Rief M, Grashoff C (December 2015). "Extracellular rigidity sensing by talin isoform-specific mechanical linkages". Nature Cell Biology. 17 (12): 1597–606. doi:10.1038/ncb3268. PMC 4662888. PMID 26523364.
  23. Kumar A, Ouyang M, Van den Dries K, McGhee EJ, Tanaka K, Anderson MD, et al. (May 2016). "Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity". The Journal of Cell Biology. 213 (3): 371–83. doi:10.1083/jcb.201510012. PMC 4862330. PMID 27161398.
  24. Kumar A, Anderson KL, Swift MF, Hanein D, Volkmann N, Schwartz MA (September 2018). "Local Tension on Talin in Focal Adhesions Correlates with F-Actin Alignment at the Nanometer Scale". Biophysical Journal. 115 (8): 1569–1579. Bibcode:2018BpJ...115.1569K. doi:10.1016/j.bpj.2018.08.045. PMC 6372196. PMID 30274833.
  25. 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. PMID 16460027.
  26. Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH, Campbell ID (January 2007). "Structural basis of integrin activation by talin". Cell. 128 (1): 171–82. doi:10.1016/j.cell.2006.10.048. PMID 17218263. S2CID 18307182.
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