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] 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 alpha-actinin.[4]Integrin receptors are involved in the attachment of adherent cells to extracellular matrices[5][6] and of lymphocytes to other cells. In these situations, talin codistributes with concentrations of integrins in the cell surface membrane.[7][8] Furthermore, in vitro binding studies suggest that integrins bind to talin, although with low affinity.[9] Talin also binds with high affinity to vinculin,[10] another cytoskeletal protein concentrated at points of cell adhesion.[11] Finally, talin is a substrate for the Ca2+-activated protease, calpain II,[12] which is also concentrated at points of cell-substratum contact.[13]
Talin Domains
Talin consists of a large C-terminal rod domain that contains bundles of α-alpha helices and an N-terminal FERM (band 4.1, ezrin, radixin, and moesin) domain with three subdomains: F1, F2, and F3.[14][15][16][17] The F3 subdomain of the FERM domain contains the highest affinity integrin-binding site for integrin β tails and is sufficient to activate integrins.[18]
Talin Activates Integrin αIIbβ3
A structure-function analysis reported recently[19] provides a cogent structural model (see top right) to explain talin-dependent integrin activation in three steps:
♦ (A) 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.
♦ (B) 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.
♦ (C) In a subsequent step, F3 engages the membrane-proximal portion of the β3 tail while maintaining its membrane-distal interactions.
References
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^Kupfer A, Singer SJ, Dennert G (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". J. Exp. Med. 163 (3): 489–98. doi:10.1084/jem.163.3.489. PMID3081676.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Burn P, Kupfer A, Singer SJ (1988). "Dynamic membrane-cytoskeletal interactions: specific association of integrin and talin arises in vivo after phorbol ester treatment of peripheral blood lymphocytes". Proc. Natl. Acad. Sci. U.S.A. 85 (2): 497–501. doi:10.1073/pnas.85.2.497. PMID3124107.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Alan D. Michelson (2006). Platelets, Second Edition. Boston: Academic Press. ISBN0-12-369367-5.
^Ruoslahti E, Pierschbacher MD (1987). "New perspectives in cell adhesion: RGD and integrins". Science. 238 (4826): 491–7. doi:10.1126/science.2821619. PMID2821619.
^Chen WT, Hasegawa E, Hasegawa T, Weinstock C, Yamada KM (1985). "Development of cell surface linkage complexes in cultured fibroblasts". J. Cell Biol. 100 (4): 1103–14. doi:10.1083/jcb.100.4.1103. PMID3884631.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Kupfer A, Singer SJ (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". J. Exp. Med. 170 (5): 1697–713. doi:10.1084/jem.170.5.1697. PMID2530300.
^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. doi:10.1038/320531a0. PMID2938015.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Burridge K, Mangeat P (1984). "An interaction between vinculin and talin". Nature. 308 (5961): 744–6. doi:10.1038/308744a0. PMID6425696.
^Geiger B (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.
^Beckerle MC, Burridge K, DeMartino GN, Croall DE (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^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 (1998). "The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane". Trends Biochem. Sci. 23 (8): 281–2. doi:10.1016/S0968-0004(98)01237-7. PMID9757824.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^García-Alvarez B, de Pereda JM, Calderwood DA, Ulmer TS, Critchley D, Campbell ID, Ginsberg MH, Liddington RC (2003). "Structural determinants of integrin recognition by talin". Mol. Cell. 11 (1): 49–58. doi:10.1016/S1097-2765(02)00823-7. PMID12535520.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Papagrigoriou E, Gingras AR, Barsukov IL, Bate N, Fillingham IJ, Patel B, Frank R, Ziegler WH, Roberts GC, Critchley DR, Emsley J (2004). "Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle". EMBO J. 23 (15): 2942–51. doi:10.1038/sj.emboj.7600285. PMID15272303.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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^Calderwood DA, Yan B, de Pereda JM, Alvarez BG, Fujioka Y, Liddington RC, Ginsberg MH (2002). "The phosphotyrosine binding-like domain of talin activates integrins". J. Biol. Chem. 277 (24): 21749–58. doi:10.1074/jbc.M111996200. PMID11932255.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
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