Fuzziness pp 50-73 | Cite as

Interplay Between Protein Order, Disorder and Oligomericity in Receptor Signaling

  • Alexander B. Sigalov
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 725)


Receptor-mediated signaling plays an important role in health and disease. Recent reports have revealed that many proteins that do not adopt globular structures under native conditions, thus termed intrinsically disordered, are involved in cell signaling. Intriguingly, physiologically relevant oligomerization of intrinsically disordered proteins (IDPs) has been recently observed and shown to exhibit unique biophysical characteristics, including the lack of significant changes in chemical shift and peak intensity upon binding. On the other hand, ligand-induced or - tuned receptor oligomerization is known to be a general feature of various cell surface receptors and to play a crucial role in signal transduction. In this work, I summarize several distinct features of protein disorder that are especially important as related to signal transduction. I also hypothesize that interactions of IDPs with their protein or lipid partners represent a general biphasic process with the electrostatic-driven „no disorder-to-order“ fast interaction which, depending on the interacting partner, may or may not be accompanied by the hydrophobic-driven slow formation of a secondary structure. Further, I suggest signaling-related functional connections between protein order, disorder and oligomericity and hypothesize that receptor oligomerization induced or tuned upon ligand binding outside the cell is translated across the membrane into protein oligomerization inside the cell, thus providing a general platform, the Signaling Chain HOmoOLigomerization (SCHOOL) platform, for receptor-mediated signaling. This structures our current multidisciplinary knowledge and views of the mechanisms governing the coupling of recognition to signal transduction and cell response. Importantly, this approach not only reveals previously unrecognized striking similarities in the basic mechanistic principles of function of numerous functionally diverse and unrelated surface membrane receptors, but also suggests the similarity between therapeutic targets, thus opening new horizons for both fundamental and clinically relevant studies.


Natural Killer Cell Natural Killer Cell Receptor Protein Disorder Receptor Oligomerization Signal Trans Ducti 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Rudd CE. Disabled receptor signaling and new primary immunodeficiency disorders. N Engl J Med 2006; 354:1874–1877.PubMedGoogle Scholar
  2. 2.
    Sigalov AB, ed. Multichain Immune Recognition Receptor Signaling: From Spatiotemporal Organization to Human Disease. New York: Springer-Verlag; 2008:357.Google Scholar
  3. 3.
    Klemm JD, Schreiber SL, Crabtree GR. Dimerization as a regulatory mechanism in signal transduction. Annu Rev Immunol 1998; 16:569–592.PubMedGoogle Scholar
  4. 4.
    Metzger H. Transmembrane signaling: the joy of aggregation. J Immunol 1992; 149:1477–1487.PubMedGoogle Scholar
  5. 5.
    Iakoucheva LM, Brown CJ, Lawson JD et al. Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 2002; 323:573–584.PubMedGoogle Scholar
  6. 6.
    Iakoucheva LM, Radivojac P, Brown CJ et al. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res 2004; 32:1037–1049.PubMedGoogle Scholar
  7. 7.
    Minezaki Y, Homma K, Nishikawa K. Intrinsically disordered regions of human plasma membrane proteins preferentially occur in the cytoplasmic segment. J Mol Biol 2007; 368:902–913.PubMedGoogle Scholar
  8. 8.
    De Biasio A, Guarnaccia C, Popovic M et al. Prevalence of intrinsic disorder in the intracellular region of human single-pass type I proteins: the case of the notch ligand Delta-4. J Proteome Res 2008; 7:2496–2506.PubMedGoogle Scholar
  9. 9.
    Sigalov A, Aivazian D, Stern L. Homooligomerization of the cytoplasmic domain of the T-cell receptor zeta chain and of other proteins containing the immunoreceptor tyrosine-based activation motif. Biochemistry 2004; 43:2049–2061.PubMedGoogle Scholar
  10. 10.
    Sigalov AB, Aivazian DA, Uversky VN et al. Lipid-binding activity of intrinsically unstructured cytoplasmic domains of multichain immune recognition receptor signaling subunits. Biochemistry 2006; 45:15731–15739.PubMedGoogle Scholar
  11. 11.
    Sigalov AB, Zhuravleva AV, Orekhov VY. Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form. Biochimie 2007; 89:419–421.PubMedGoogle Scholar
  12. 12.
    Uversky VN, Gillespie JR, Fink AL. Why are „natively unfolded“ proteins unstructured under physiologic conditions? Proteins 2000; 41:415–427.PubMedGoogle Scholar
  13. 13.
    Le Gall T, Romero PR, Cortese MS et al. Intrinsic disorder in the protein data bank. J Biomol Struct Dyn 2007; 24:325–342.PubMedGoogle Scholar
  14. 14.
    Dunker AK, Brown CJ, Lawson JD et al. Intrinsic disorder and protein function. Biochemistry 2002; 41:6573–6582.PubMedGoogle Scholar
  15. 15.
    Linding R, Jensen LJ, Diella F et al. Protein disorder prediction: implications for structural proteomics. Structure 2003; 11:1453–1459.PubMedGoogle Scholar
  16. 16.
    Ward JJ, McGuffin LJ, Bryson K et al. The DISOPRED server for the prediction of protein disorder. Bioinformatics 2004; 20:2138–2139.PubMedGoogle Scholar
  17. 17.
    Prilusky J, Felder CE, Zeev-Ben-Mordehai T et al. FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 2005; 21:3435–3438.PubMedGoogle Scholar
  18. 18.
    Oldfield CJ, Cheng Y, Cortese MS et al. Comparing and combining predictors of mostly disordered proteins. Biochemistry 2005; 44:1989–2000.PubMedGoogle Scholar
  19. 19.
    Receveur-Brechot V, Bourhis JM, Uversky VN et al. Assessing protein disorder and induced folding. Proteins 2006; 62:24–45.PubMedGoogle Scholar
  20. 20.
    Dyson HJ, Wright PE. Equilibrium NMR studies of unfolded and partially folded proteins. Nat Struct Biol 1998; 5 Suppl:499–503.PubMedGoogle Scholar
  21. 21.
    Dyson HJ, Wright PE. Unfolded proteins and protein folding studied by NMR. Chem Rev 2004; 104:3607–3622.PubMedGoogle Scholar
  22. 22.
    Dunker AK, Silman I, Uversky VN et al. Function and structure of inherently disordered proteins. Curr Opin Struct Biol 2008; 18:756–764.PubMedGoogle Scholar
  23. 23.
    Dyson HJ, Wright PE. Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 2005; 6:197–208.PubMedGoogle Scholar
  24. 24.
    Vucetic S, Xie H, Iakoucheva LM et al. Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes and coding sequence diversities correlated with long disordered regions. J Proteome Res 2007; 6:1899–1916.PubMedGoogle Scholar
  25. 25.
    Xie H, Vucetic S, Iakoucheva LM et al. Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications and diseases associated with intrinsically disordered proteins. J Proteome Res 2007; 6:1917–1932.PubMedGoogle Scholar
  26. 26.
    Xie H, Vucetic S, Iakoucheva LM et al. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J Proteome Res 2007; 6:1882–1898.PubMedGoogle Scholar
  27. 27.
    Gsponer J, Futschik ME, Teichmann SA et al. Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Science 2008; 322:1365–1368.PubMedGoogle Scholar
  28. 28.
    Tompa P. The interplay between structure and function in intrinsically unstructured proteins. FEBS Lett 2005; 579:3346–3354.PubMedGoogle Scholar
  29. 29.
    Uversky VN. What does it mean to be natively unfolded? Eur J Biochem 2002; 269:2–12.PubMedGoogle Scholar
  30. 30.
    Uversky VN, Dunker AK. Biochemistry. Controlled chaos. Science 2008; 322:1340–1341.PubMedGoogle Scholar
  31. 31.
    Tompa P. Intrinsically unstructured proteins. Trends Biochem Sci 2002; 27:527–533.PubMedGoogle Scholar
  32. 32.
    Tompa P, Fuxreiter M. Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 2008; 33:2–8.PubMedGoogle Scholar
  33. 33.
    Demchenko AP. Recognition between flexible protein molecules: induced and assisted folding. J Mol Recognit 2001; 14:42–61.PubMedGoogle Scholar
  34. 34.
    Dyson HJ, Wright PE. Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 2002; 12:54–60.PubMedGoogle Scholar
  35. 35.
    Xu C, Gagnon E, Call ME et al. Regulation of T-cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. Cell 2008; 135:702–713.PubMedGoogle Scholar
  36. 36.
    Aivazian DA, Stern LJ. Phosphorylation of T-cell receptor zeta is regulated by a lipid dependent folding transition. Nat Struct Biol 2000; 7:1023–1026.PubMedGoogle Scholar
  37. 37.
    Radhakrishnan I, Perez-Alvarado GC, Dyson HJ et al. Conformational preferences in the Ser133-phosphorylated and nonphosphorylated forms of the kinase inducible transactivation domain of CREB. FEBS Lett 1998; 430:317–322.PubMedGoogle Scholar
  38. 38.
    Richards JP, Bachinger HP, Goodman RH et al. Analysis of the structural properties of cAMP-responsive element-binding protein (CREB) and phosphorylated CREB. J Biol Chem 1996; 271:13716–13723.PubMedGoogle Scholar
  39. 39.
    Radhakrishnan I, Perez-Alvarado GC, Parker D et al. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell 1997; 91:741–752.PubMedGoogle Scholar
  40. 40.
    Fletcher CM, McGuire AM, Gingras AC et al. 4E binding proteins inhibit the translation factor eIF4E without folded structure. Biochemistry 1998; 37:9–15.PubMedGoogle Scholar
  41. 41.
    Fletcher CM, Wagner G. The interaction of eIF4E with 4E-BP1 is an induced fit to a completely disordered protein. Protein Sci 1998; 7:1639–1642.PubMedGoogle Scholar
  42. 42.
    Tomoo K, Matsushita Y, Fujisaki H et al. Structural basis for mRNA Cap-Binding regulation of eukaryotic initiation factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal structural and molecular dynamics simulation methods. Biochim Biophys Acta 2005; 1753:191–208.PubMedGoogle Scholar
  43. 43.
    Bourhis JM, Receveur-Brechot V, Oglesbee M et al. The intrinsically disordered C-terminal domain of the measles virus nucleoprotein interacts with the C-terminal domain of the phosphoprotein via two distinct sites and remains predominantly unfolded. Protein Sci 2005; 14:1975–1992.PubMedGoogle Scholar
  44. 44.
    Zhou P, Lugovskoy AA, McCarty JS et al. Solution structure of DFF40 and DFF45 N-terminal domain complex and mutual chaperone activity of DFF40 and DFF45. Proc Natl Acad Sci USA 2001; 98:6051–6055.PubMedGoogle Scholar
  45. 45.
    Demarest SJ, Martinez-Yamout M, Chung J et al. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 2002; 415:549–553.PubMedGoogle Scholar
  46. 46.
    Singh VK, Pacheco I, Uversky VN et al. Intrinsically disordered human C/EBP homologous protein regulates biological activity of colon cancer cells during calcium stress. J Mol Biol 2008; 380:313–326.PubMedGoogle Scholar
  47. 47.
    Danielsson J, Liljedahl L, Barany-Wallje E et al. The intrinsically disordered RNR inhibitor Sml1 is a dynamic dimer. Biochemistry 2008; 47:13428–13437.PubMedGoogle Scholar
  48. 48.
    Lanza DC, Silva JC, Assmann EM et al. Human FEZ1 has characteristics of a natively unfolded protein and dimerizes in solution. Proteins 2009; 74:104–121.PubMedGoogle Scholar
  49. 49.
    Simon SM, Sousa FJ, Mohana-Borges R et al. Regulation of Escherichia coli SOS mutagenesis by dimeric intrinsically disordered umuD gene products. Proc Natl Acad Sci USA 2008; 105:1152–1157.PubMedGoogle Scholar
  50. 50.
    Sigalov AB. Protein intrinsic disorder and oligomericity in cell signaling. Mol Biosyst 2010; 6(3):451–461PubMedGoogle Scholar
  51. 51.
    Sigalov AB, Hendricks GM. Membrane binding mode of intrinsically disordered cytoplasmic domains of T-cell receptor signaling subunits depends on lipid composition. Biochem Biophys Res Commun 2009; 389:388–393.PubMedGoogle Scholar
  52. 52.
    Duchardt E, Sigalov AB, Aivazian D et al. Structure induction of the T-cell receptor zeta-chain upon lipid binding investigated by NMR spectroscopy. Chembiochem 2007; 8:820–827.PubMedGoogle Scholar
  53. 53.
    Laczko I, Hollosi M, Vass E et al. Conformational effect of phosphorylation on T-cell receptor/CD3 zeta-chain sequences. Biochem Biophys Res Commun 1998; 242:474–479.PubMedGoogle Scholar
  54. 54.
    Gerlach H, Laumann V, Martens S et al. HIV-1 Nef membrane association depends on charge, curvature, composition and sequence. Nat Chem Biol 2009; DOI:10.1038/nchembio.268.Google Scholar
  55. 55.
    Langner M, Kubica K. The electrostatics of lipid surfaces. Chem Phys Lipids 1999; 101:3–35.PubMedGoogle Scholar
  56. 56.
    Shoemaker SD, Vanderlick TK. Intramembrane electrostatic interactions destabilize lipid vesicles. Biophys J 2002; 83:2007–2014.PubMedGoogle Scholar
  57. 57.
    Hazy E, Tompa P. Limitations of induced folding in molecular recognition by intrinsically disordered proteins. Chem Phys Chem 2009; 10:1415–1419.PubMedGoogle Scholar
  58. 58.
    Sigalov AB, Kim WM, Saline M et al. The intrinsically disordered cytoplasmic domain of the T-cell receptor zeta chain binds to the Nef Protein of simian immunodeficiency virus without a disorder-to-order transition. Biochemistry 2008; 47:12942–12944.PubMedGoogle Scholar
  59. 59.
    Mittag T, Kay LE, Forman-Kay JD. Protein dynamics and conformational disorder in molecular recognition. J Mol Recognit 2009; DOI: 10.1002/jmr.961.Google Scholar
  60. 60.
    Schaefer TM, Bell I, Fallert BA et al. The T-cell receptor zeta chain contains two homologous domains with which simian immunodeficiency virus Nef interacts and mediates down-modulation. J Virol 2000; 74:3273–3283.PubMedGoogle Scholar
  61. 61.
    Kuhns MS, Davis MM. The safety on the TCR trigger. Cell 2008; 135:594–596.PubMedGoogle Scholar
  62. 62.
    Blumenthal R, Clague MJ, Durell SR et al. Membrane fusion. Chem Rev 2003; 103:53–69.PubMedGoogle Scholar
  63. 63.
    Bullough PA, Hughson FM, Skehel JJ et al. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 1994; 371:37–43.PubMedGoogle Scholar
  64. 64.
    Carr CM, Kim PS. A spring-loaded mechanism for the conformational change of influenza hemagglutinin. Cell 1993; 73:823–832.PubMedGoogle Scholar
  65. 65.
    Hegyi H, Schad E, Tompa P. Structural disorder promotes assembly of protein complexes. BMC Struct Biol 2007; 7:65.PubMedGoogle Scholar
  66. 66.
    Espinoza-Fonseca LM. Reconciling binding mechanisms of intrinsically disordered proteins. Biochem Biophys Res Commun 2009; 382:479–482.PubMedGoogle Scholar
  67. 67.
    Kumar S, Ma B, Tsai CJ et al. Folding and binding cascades: dynamic landscapes and population shifts. Protein Sci 2000; 9:10–19.PubMedGoogle Scholar
  68. 68.
    Tsai CJ, Ma B, Sham YY et al. Structured disorder and conformational selection. Proteins 2001; 44:418–427.PubMedGoogle Scholar
  69. 69.
    Sigalov AB. Multichain immune recognition receptor signaling: different players, same game? Trends Immunol 2004; 25:583–589.PubMedGoogle Scholar
  70. 70.
    Sigalov AB. Immune cell signaling: a novel mechanistic model reveals new therapeutic targets. Trends Pharmacol Sci 2006; 27:518–524.PubMedGoogle Scholar
  71. 71.
    Sigalov AB. SCHOL model and new targeting strategies. Adv Exp Med Biol 2008; 640:268–311.PubMedGoogle Scholar
  72. 72.
    Sigalov AB. Signaling chain homooligomerization (SCHOOL) model. Adv Exp Med Biol 2008; 640:121–163.PubMedGoogle Scholar
  73. 73.
    Sigalov AB. The SCHOOL of nature. I. Transmembrane signaling. Self/Nonself 2010; 1:4–39.PubMedGoogle Scholar
  74. 74.
    Borg M, Mittag T, Pawson T et al. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. Proc Natl Acad Sci USA 2007; 104:9650–9655.PubMedGoogle Scholar
  75. 75.
    Keegan AD, Paul WE. Multichain immune recognition receptors: similarities in structure and signaling pathways. Immunol Today 1992; 13:63–68.PubMedGoogle Scholar
  76. 76.
    Sigalov A. Multi-chain immune recognition receptors: spatial organization and signal transduction. Semin Immunol 2005; 17:51–64.PubMedGoogle Scholar
  77. 77.
    Cooper JA, Qian H. A mechanism for SRC kinase-dependent signaling by noncatalytic receptors. Biochemistry 2008; 47:5681–5688.PubMedGoogle Scholar
  78. 78.
    Weiss A, Schlessinger J. Switching signals on or off by receptor dimerization. Cell 1998; 94:277–280.PubMedGoogle Scholar
  79. 79.
    Lemmon MA, Schlessinger J. Regulation of signal transduction and signal diversity by receptor oligomerization. Trends Biochem Sci 1994; 19:459–463.PubMedGoogle Scholar
  80. 80.
    Bennasroune A, Fickova M, Gardin A et al. Transmembrane peptides as inhibitors of ErbB receptor signaling. Mol Biol Cell 2004; 15:3464–3474.PubMedGoogle Scholar
  81. 81.
    Siegel RM, Muppidi JR, Sarker M et al. SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor-induced apoptosis at the plasma membrane. J Cell Biol 2004; 167:735–744.PubMedGoogle Scholar
  82. 82.
    Uversky VN. Amyloidogenesis of natively unfolded proteins. Curr Alzheimer Res 2008; 5:260–287.PubMedGoogle Scholar
  83. 83.
    Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem 2000; 69:373–398.PubMedGoogle Scholar
  84. 84.
    Zhou T, Mountz JD, Kimberly RP. Immunobiology of tumor necrosis factor receptor superfamily. Immunol Res 2002; 26:323–336.PubMedGoogle Scholar
  85. 85.
    Li MO, Wan YY, Sanjabi S et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006; 24:99–146.PubMedGoogle Scholar
  86. 86.
    Jiang G, Hunter T. Receptor signaling: when dimerization is not enough. Curr Biol 1999; 9:R568–R571.PubMedGoogle Scholar
  87. 87.
    Marianayagam NJ, Sunde M, Matthews JM. The power of two: protein dimerization in biology. Trends Biochem Sci 2004; 29:618–625.PubMedGoogle Scholar
  88. 88.
    Chan FK. Three is better than one: preligand receptor assembly in the regulation of TNF receptor signaling. Cytokine 2007; 37:101–107.PubMedGoogle Scholar
  89. 89.
    Dosch DD, Ballmer-Hofer K. Transmembrane domain-mediated orientation of receptor monomers in active VEGFR-2 dimers. FASEB J 2009; DOI:10.1096/fj.09-132670.Google Scholar
  90. 90.
    Geijtenbeek TB, Gringhuis SI. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 2009; 9:465–479.PubMedGoogle Scholar
  91. 91.
    Krogsgaard M, Davis MM. How T-cells’ see’ antigen. Nat Immunol 2005; 6:239–245.PubMedGoogle Scholar
  92. 92.
    DeFranco AL. B-cell activation 2000. Immunol Rev 2000; 176:5–9.PubMedGoogle Scholar
  93. 93.
    Dal Porto JM, Gauld SB, Merrell KT et al. B-cell antigen receptor signaling 101. Mol Immunol 2004; 41:599–613.Google Scholar
  94. 94.
    Takai T. Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol 2005; 25:1–18.PubMedGoogle Scholar
  95. 95.
    Takai T. Fc receptors: their diverse functions in immunity and immune disorders. Springer Semin Immunopathol 2006; 28:303–304.PubMedGoogle Scholar
  96. 96.
    Colonna M, Nakajima H, Navarro F et al. A novel family of Ig-like receptors for HLA class I molecules that modulate function of lymphoid and myeloid cells. J Leukoc Biol 1999; 66:375–381.PubMedGoogle Scholar
  97. 97.
    Borrego F, Kabat J, Kim DK et al. Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol Immunol 2002; 38:637–660.PubMedGoogle Scholar
  98. 98.
    Moroi M, Jung SM. Platelet glycoprotein VI: its structure and function. Thromb Res 2004; 114:221–233.PubMedGoogle Scholar
  99. 99.
    Barclay AN, Brown MH. The SIRP family of receptors and immune regulation. Nat Rev Immunol 2006; 6:457–464.PubMedGoogle Scholar
  100. 100.
    Kanazawa N, Tashiro K, Miyachi Y. Signaling and immune regulatory role of the dendritic cell immunoreceptor (DCIR) family lectins: DCIR, DCAR, dectin-2 and BDCA-2. Immunobiology 2004; 209:179–190.PubMedGoogle Scholar
  101. 101.
    Biassoni R, Cantoni C, Falco M et al. Human natural killer cell activating receptors. Mol Immunol 2000; 37:1015–1024.PubMedGoogle Scholar
  102. 102.
    Biassoni R, Cantoni C, Marras D et al. Human natural killer cell receptors: insights into their molecular function and structure. J Cell Mol Med 2003; 7:376–387.PubMedGoogle Scholar
  103. 103.
    Aoki N, Kimura S, Xing Z. Role of DAP12 in innate and adaptive immune responses. Curr Pharm Des 2003; 9:7–10.PubMedGoogle Scholar
  104. 104.
    Bakker AB, Baker E, Sutherland GR et al. Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells. Proc Natl Acad Sci USA 1999; 96:9792–9796.PubMedGoogle Scholar
  105. 105.
    van den Berg TK, Yoder JA, Litman GW. On the origins of adaptive immunity: innate immune receptors join the tale. Trends Immunol 2004; 25:11–16.PubMedGoogle Scholar
  106. 106.
    Klesney-Tait J, Turnbull IR, Colonna M. The TREM receptor family and signal integration. Nat Immunol 2006; 7:1266–1273.PubMedGoogle Scholar
  107. 107.
    Takai T. Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology 2005; 115:433–440.PubMedGoogle Scholar
  108. 108.
    Nakahashi C, Tahara-Hanaoka S, Totsuka N et al. Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP12 and FcRgamma chain on peritoneal macrophages. J Immunol 2007; 178:765–770.PubMedGoogle Scholar
  109. 109.
    Fujimoto M, Takatsu H, Ohno H. CMRF-35-like molecule-5 constitutes novel paired receptors, with CMRF-35-like molecule-1, to transduce activation signal upon association with FcRgamma. Int Immunol 2006; 18:1499–1508.PubMedGoogle Scholar
  110. 110.
    Stewart CA, Vivier E, Colonna M. Strategies of natural killer cell recognition and signaling. Curr Top Microbiol Immunol 2006; 298:1–21.PubMedGoogle Scholar
  111. 111.
    Reth M. Antigen receptor tail clue. Nature 1989; 338:383–384.PubMedGoogle Scholar
  112. 112.
    Songyang Z, Shoelson SE, Chaudhuri M et al. SH2 domains recognize specific phosphopeptide sequences. Cell 1993; 72:767–778.PubMedGoogle Scholar
  113. 113.
    Wu J, Cherwinski H, Spies T et al. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. J Exp Med 2000; 192:1059–1068.PubMedGoogle Scholar
  114. 114.
    Manolios N, Bonifacino JS, Klausner RD. Transmembrane helical interactions and the assembly of the T-cell receptor complex. Science 1990; 249:274–277.PubMedGoogle Scholar
  115. 115.
    Call ME, Pyrdol J, Wiedmann M et al. The organizing principle in the formation of the T-cell receptor-CD3 complex. Cell 2002; 111:967–979.PubMedGoogle Scholar
  116. 116.
    Michnoff CH, Parikh VS, Lelsz DL et al. Mutations within the NH2-terminal transmembrane domain of membrane immunoglobulin (Ig) M alters Ig alpha and Ig beta association and signal transduction. J Biol Chem 1994; 269:24237–24244.PubMedGoogle Scholar
  117. 117.
    Daeron M. Fc receptor biology. Annu Rev Immunol 1997; 15:203–234.PubMedGoogle Scholar
  118. 118.
    Feng J, Garrity D, Call ME et al. Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity 2005; 22:427–438.PubMedGoogle Scholar
  119. 119.
    Feng J, Call ME, Wucherpfennig KW. The assembly of diverse immune receptors is focused on a polar membrane-embedded interaction site. PLoS Biol 2006; 4:e142.PubMedGoogle Scholar
  120. 120.
    Bakema JE, de Haij S, den Hartog-Jager CF et al. Signaling through mutants of the IgA receptor CD89 and consequences for Fc receptor gamma-chain interaction. J Immunol 2006; 176:3603–3610.PubMedGoogle Scholar
  121. 121.
    Varin-Blank N, Metzger H. Surface expression of mutated subunits of the high affinity mast cell receptor for IgE. J Biol Chem 1990; 265:15685–15694.PubMedGoogle Scholar
  122. 122.
    Stevens TL, Blum JH, Foy SP et al. A mutation of the mu transmembrane that disrupts endoplasmic reticulum retention. Effects on association with accessory proteins and signal transduction. J Immunol 1994; 152:4397–4406.PubMedGoogle Scholar
  123. 123.
    Zidovetzki R, Rost B, Pecht I. Role of transmembrane domains in the functions of B-and T-cell receptors. Immunol Lett 1998; 64:97–107.PubMedGoogle Scholar
  124. 124.
    Blum JH, Stevens TL, DeFranco AL. Role of the mu immunoglobulin heavy chain transmembrane and cytoplasmic domains in B-cell antigen receptor expression and signal transduction. J Biol Chem 1993; 268:27236–27245.PubMedGoogle Scholar
  125. 125.
    Ra C, Jouvin MH, Kinet JP. Complete structure of the mouse mast cell receptor for IgE (Fc epsilon RI) and surface expression of chimeric receptors (rat-mouse-human) on transfected cells. J Biol Chem 1989; 264:15323–15327.PubMedGoogle Scholar
  126. 126.
    Schamel WW, Arechaga I, Risueno RM et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J Exp Med 2005; 202:493–503.PubMedGoogle Scholar
  127. 127.
    Berlanga O, Bori-Sanz T, James JR et al. Glycoprotein VI oligomerization in cell lines and platelets. J Thromb Haemost 2007; 5:1026–1033.PubMedGoogle Scholar
  128. 128.
    Loregian A, Palu G. Disruption of protein-protein interactions: towards new targets for chemotherapy. J Cell Physiol 2005; 204:750–762.PubMedGoogle Scholar
  129. 129.
    Hershberger SJ, Lee SG, Chmielewski J. Scaffolds for blocking protein-protein interactions. Curr Top Med Chem 2007; 7:928–942.PubMedGoogle Scholar
  130. 130.
    Sillerud LO, Larson RS. Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction. Curr Protein Pept Sci 2005; 6:151–169.PubMedGoogle Scholar
  131. 131.
    Sigalov AB. Transmembrane interactions as immunotherapeutic targets: lessons from viral pathogenesis. Adv Exp Med Biol 2007; 601:335–344.PubMedGoogle Scholar
  132. 132.
    Sigalov AB. New therapeutic strategies targeting transmembrane signal transduction in the immune system. Cell Adh Migr 2010; 4:255–267.PubMedGoogle Scholar
  133. 133.
    Sigalov AB. Novel mechanistic concept of platelet inhibition. Expert Opin Ther Targets 2008; 12:677–692.PubMedGoogle Scholar
  134. 134.
    Sigalov AB. Inhibiting Collagen-induced Platelet Aggregation and Activation with Peptide Variants. US 12/001,258 and PCT PCT/US2007/025389 patent applications filed on 12/11/2007 and 12/12/2007, respectively, claiming a priority to US 60/874,694 provisional patent application filed on 12/13/2006.Google Scholar
  135. 135.
    Sigalov AB. Novel mechanistic insights into viral modulation of immune receptor signaling. PLoS Pathog 2009; 5:e1000404.PubMedGoogle Scholar
  136. 136.
    Wang XM, Djordjevic JT, Kurosaka N et al. T-cell antigen receptor peptides inhibit signal transduction within the membrane bilayer. Clin Immunol 2002; 105:199–207.PubMedGoogle Scholar
  137. 137.
    Quintana FJ, Gerber D, Kent SC et al. HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T-cell activation. J Clin Invest 2005; 115:2149–2158.PubMedGoogle Scholar
  138. 138.
    Sigalov AB. Interaction between HIV gp41 fusion peptide and T-cell receptor: putting the puzzle pieces back together. FASEB J 2007; 21:1633–1634; author reply 1635.PubMedGoogle Scholar
  139. 139.
    Sigalov AB. More on: glycoprotein VI oligomerization: a novel concept of platelet inhibition. J Thromb Haemost 2007; 5:2310–2312.PubMedGoogle Scholar
  140. 140.
    Allez M, Tieng V, Nakazawa A et al. CD4+NKG2D+ T-cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology 2007; 132:2346–2358.PubMedGoogle Scholar
  141. 141.
    Ito Y, Kanai T, Totsuka T et al. Blockade of NKG2D signaling prevents the development of murine CD4+ T-cell-mediated colitis. Am J Physiol Gastrointest Liver Physiol 2008; 294:G199–207.PubMedGoogle Scholar
  142. 142.
    Appel RD, Bairoch A, Hochstrasser DF. A new generation of information retrieval tools for biologists: the example of the ExPASy WWW server. Trends Biochem Sci 1994; 19:258–260.PubMedGoogle Scholar
  143. 143.
    Kyte J, Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol 1982; 157:105–132.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Alexander B. Sigalov
    • 1
  1. 1.SignaBlok, Inc.ShrewsburyUSA

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