Pharmacological Interference with Protein-Protein Interactions Mediated by Coiled-Coil Motifs

  • H. M. Strauss
  • S. Keller
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 186)


Coiled coils are bundles of intertwined α-helices that provide proteinprotein interaction sites for the dynamic assembly and disassembly of protein complexes. The coiled-coil motif combines structural versatility and adaptability with mechanical strength and specificity. Multimeric proteins that rely on coiledcoil interactions are structurally and functionally very diverse, ranging from simple homodimeric transcription factors to elaborate heteromultimeric scaffolding clusters. Several coiled-coil-bearing proteins are of outstanding pharmacological importance, most notably SNARE proteins involved in vesicular trafficking of neurotransmitters and viral fusion proteins. Together with their crucial roles in many physiological and pathological processes, the structural simplicity and reversible nature of coiled-coil associations render them a promising target for pharmacological interference, as successfully exemplified by botulinum toxins and viral fusion inhibitors.

The α-helical coiled coil is a ubiquitous protein domain that mediates highly specific homo- and heteromeric protein-protein interactions among a wide range of proteins. The coiled-coil motif was first proposed by Crick on the basis of X-ray diffraction data on α-keratin more than 50 years ago (Crick 1952, 1953) and nowadays belongs to the best-characterized protein interaction modules. By definition, a coiled coil is an oligomeric protein assembly consisting of several right-handed amphipathic α-helices that wind around each other into a superhelix (or a supercoil) in which the hydrophobic surfaces of the constituent helices are in continuous contact, forming a hydrophobic core. Both homomeric and heteromeric coiled coils with different stoichiometries are possible, and the helices can be aligned in either a parallel or an antiparallel topology (Harbury et al. 1993, 1994). Stoichiometry and topology are governed by the primary structure, that is, the sequence of the polypeptide chains, and a given protein can participate in multiple assemblydisassembly equilibria among several coiled coils differing in stoichiometry and topology (Portwich et al. 2007).

Protein complexes whose oligomeric quaternary structures — and, hence, biological activities — depend on coiled-coil interactions include transcription factors, tRNA synthetases (Biou et al. 1994; Cusack et al. 1990), cytoskeletal and signal-transduction proteins, enzyme complexes, proteins involved in vesicular trafficking, viral coat proteins, and membrane proteins (Langosch and Heringa 1998). It is thus not surprising that coiled-coil motifs have gained great attention as potential targets for modulating protein-protein interactions implicated in a large number of diseases.

In this review, we will first discuss some fundamental functional and structural aspects of a simple and well-characterized representative of coiled-coil transcription factors (Sect. 1) before considering two more complex coiled coils found in scaffolding proteins involved in mitosis and meiosis and vesicular trafficking Sect. 2). This will set the stage for addressing the role of coiled coils in viral infection (Sect. 3) as well as strategies of interfering with such protein-protein interactions therapeutically (Sect. 4 and 5).


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  1. Alber T (1992) Structure of the leucine zipper. Curr Opin Genet Dev 2:205–210PubMedCrossRefGoogle Scholar
  2. Baker KA, Dutch RE, Lamb RA, Jardetzky TS (1999) Structural basis for paramyxovirus-mediated membrane fusion. Mol Cell 3:309–319PubMedCrossRefGoogle Scholar
  3. Bennett MK (1995) SNAREs and the specificity of transport vesicle targeting. Curr Opin Cell Biol 7:581–586PubMedCrossRefGoogle Scholar
  4. Bezprozvanny I, Scheller RH, Tsien RW (1995) Functional impact of syntaxin on gating of N-type and Q-type calcium channels. Nature 378:623–626PubMedCrossRefGoogle Scholar
  5. Biou V, Yaremchuk A, Tukalo M, Cusack S (1994) The 2.9 Å crystal structure of T. thermophilus seryl-tRNA synthetase complexed with tRNA(Ser). Science 263:1404–1410PubMedCrossRefGoogle Scholar
  6. Bullough PA, Hughson FM, Skehel JJ, Wiley DC (1994) Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371:37–43PubMedCrossRefGoogle Scholar
  7. Carr CM, Kim PS (1993) A spring-loaded mechanism for the conformational change of influenza hemagglutinin. Cell 73:823–832PubMedCrossRefGoogle Scholar
  8. Chan DC, Fass D, Berger JM, Kim PS (1997) Core structure of gp41 from the HIV envelope glycoprotein. Cell 89:263–273PubMedCrossRefGoogle Scholar
  9. Chen J, Wharton SA, Weissenhorn W, Calder LJ, Hughson FM, Skehel JJ, Wiley DC (1995) A soluble domain of the membrane-anchoring chain of influenza virus hemagglutinin (HA2) folds in Escherichia coli into the low-pH-induced confirmation. Proc Natl Acad Sci USA 92:12205–12209PubMedCrossRefGoogle Scholar
  10. Chen J, Lee KH, Steinhauer DA, Stevens DJ, Skehel JJ, Wiley DC (1998) Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation. Cell 95:409–417PubMedCrossRefGoogle Scholar
  11. Chernomordik LV, Kozlov MM (2005) Membrane hemifusion: crossing a chasm in two leaps. Cell 123:375–382PubMedCrossRefGoogle Scholar
  12. Ciferri C, De Luca J, Monzani S, Ferrari KJ, Ristic D, Wyman C, Stark H, Kilmartin J, Salmon ED, Musacchio A (2005) Architecture of the human ndc80-hec1 complex, a critical constituent of the outer kinetochore. J Biol Chem 280:29088–29095PubMedCrossRefGoogle Scholar
  13. Cleveland DW, Mao Y, Sullivan KF (2003) Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112:407–421PubMedCrossRefGoogle Scholar
  14. Contegno F, Cioce M, Pelicci PG, Minucci S (2002) Targeting protein inactivation through an oligomerization chain reaction. Proc Natl Acad Sci USA 99:1865–1869PubMedCrossRefGoogle Scholar
  15. Conway JF, Parry DA (1990) Structural features in the heptad substructure and longer range repeats of two-stranded α-fibrous proteins. Int J Biol Macromol 12:328–334PubMedCrossRefGoogle Scholar
  16. Conway JF, Parry DA (1991) Three-stranded α-fibrous proteins: the heptad repeat and its implications for structure. Int J Biol Macromol 13:14–16PubMedCrossRefGoogle Scholar
  17. Crick FHC (1952) Is α-keratin a coiled coil? Nature 170:882–883PubMedCrossRefGoogle Scholar
  18. Crick FH (1953) The packing of α-helices: simple coiled coils. Acta Crystallogr 6:689–698CrossRefGoogle Scholar
  19. Cusack S, Berthet-Colominas C, Hartlein M, Nassar N, Leberman R (1990) A second class of synthetase structure revealed by X-ray analysis of Escherichia coli seryl-tRNA synthetase at 2.5 Å. Nature 347:249–255PubMedCrossRefGoogle Scholar
  20. Dwyer JJ, Wilson KL, Davison DK, Freel SA, Seedorff JE, Wring SA, Tvermoes NA, Matthews TJ, Greenberg ML, Delmedico MK (2007) Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus. Proc Natl Acad Sci USA 104:12772–12777PubMedCrossRefGoogle Scholar
  21. Ellenberger TE, Brandl CJ, Struhl K, Harrison, SC (1992) The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted r helices: crystal structure of the protein–DNA complex. Cell 71:1223–1237PubMedCrossRefGoogle Scholar
  22. Eron JJ, Gulick RM, Bartlett JA, Merigan T, Arduino R, Kilby JM, Yangco B, Diers A, Drobnes C, DeMasi R, Greenberg M, Melby T, Raskino C, Rusnak P, Zhang Y, Spence R Miralles GD (2004) Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV. J Infect Dis 189:1075–1083PubMedCrossRefGoogle Scholar
  23. Fasshauer D, Sutton RB, Brünger AT, Jahn R (1998) Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs. Proc Natl Acad Sci USA 95:15781–15786PubMedCrossRefGoogle Scholar
  24. Gillingham AK, Munro S (2003) Long coiled-coil proteins and membrane traffic. Biochim Biophys Acta 1641:71–85PubMedCrossRefGoogle Scholar
  25. Glover JN, Harrison SC (1995) Crystal structure of the heterodimeric bZIP transcription factor c-Fos–c-Jun bound to DNA. Nature 373:257–261PubMedCrossRefGoogle Scholar
  26. Goldenberg DM (2003) Advancing role of radiolabeled antibodies in the therapy of cancer. Cancer Immunol Immunother 52:281–296PubMedGoogle Scholar
  27. Gonzalez L, Jr, Woolfson, DN, Alber T (1996) Buried polar residues and structural specificity in the GCN4 leucine zipper. Nat Struct Biol 3:1011–1018PubMedCrossRefGoogle Scholar
  28. Goodwin DA, Meares CF (2001) Advances in pretargeting biotechnology. Biotechnol Adv 19:435–450PubMedCrossRefGoogle Scholar
  29. Hanson PI, Heuser JE, Jahn R (1997) Neurotransmitter release–four years of SNARE complexes. Curr Opin Neurobiol 7:310–315PubMedCrossRefGoogle Scholar
  30. Harbury PB, Zhang T, Kim PS, Alber T (1993) A switch between two-, three-, and four-stranded coiled coils in GCN4 leucine zipper mutants. Science 262:1401–1407PubMedCrossRefGoogle Scholar
  31. Harbury PB, Kim PS, Alber T (1994) Crystal structure of an isoleucine-zipper trimer. Nature 371:80–83PubMedCrossRefGoogle Scholar
  32. Hinnebusch AG (1992) General and pathway-specific regulatory mechanisms controlling the synthesis of amino acid biosynthetic enzymes in Saccharomyces cerevisae. In: Broach JR, Jones EW, Pringle JR (eds) The molecular and cellular biology of the yeast Saccharomyces: gene expression. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 319–414Google Scholar
  33. Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot Cell 1:22–32PubMedCrossRefGoogle Scholar
  34. Hodges RS, Sodek J, Smillie LB, Jurasek L (1972) Tropomyosin: amino acid sequence and coiled coil structure. Cold Spring Harbor Symp Quant Biol 37:299–310Google Scholar
  35. Hodges RS, Zhu BY, Zhou NE, Mant CT (1994) Reversed-phase liquid chromatography as a useful probe of hydrophobic interactions involved in protein folding and protein stability. J Chromatogr A 676: 3–15PubMedCrossRefGoogle Scholar
  36. Hurst HC (1994) Transcription factors 1: bZIP proteins. Protein Profile 1(2):123–168PubMedGoogle Scholar
  37. Hurst HC (1995) Transcription factors 1: bZIP proteins. Protein Profile 2(2):101–168PubMedGoogle Scholar
  38. Ito T, Suzuki Y, Takada A, Kawamoto A, Otsuki K, Masuda H, Yamada M, Suzuki T, Kida H, Kawaoka Y (1997) Differences in sialic acid–galactose linkages in the chicken egg amnion and allantois influence human influenza virus receptor specificity and variant selection. J Virol 71:3357–3362PubMedGoogle Scholar
  39. Jahn R, Niemann H (1994) Molecular mechanisms of clostridial neurotoxins. Ann NY Acad Sci 733:245–255PubMedCrossRefGoogle Scholar
  40. Jiang S, Lin K, Strick N, Neurath, AR (1994) HIV-1 inhibition by a peptide. Nature 365:113CrossRefGoogle Scholar
  41. Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath AK (2004) N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob Agents Chemother 48:4349–4359PubMedCrossRefGoogle Scholar
  42. Jin BS, Lee WK, Ahn K, Lee MK, Yu YG (2005) High-throughput screening method of inhibitors that block the interaction between two helical regions of HIV-1 gp41. Biomol Screen 10:13–19CrossRefGoogle Scholar
  43. Keller W, König P, Richmond TJ (1995) Crystal structure of a bZIP/DNA complex at 2.2 Å: determinants of DNA specific recognition. J Mol Biol 254:657–667PubMedCrossRefGoogle Scholar
  44. Knappenberger JA, Smith JE, Thorpe SH, Zitzewitz JA, Matthews CR (2002) A buried polar residue in the hydrophobic interface of the coiled coil peptide, GCN4–p1, plays a thermodynamic, not a kinetic role in folding. J Mol Biol 321:1–6PubMedCrossRefGoogle Scholar
  45. König P, Richmond TJ (1993) The X-ray structure of the GCN4-bZIP bound to ATF/CREB site DNA shows the complex depends on DNA flexibility. J Mol Biol 233:139–154PubMedCrossRefGoogle Scholar
  46. Krylov D, Mikhailenko I, Vinson C (1994) A thermodynamic scale for leucine zipper stability and dimerization specificity: e and g interhelical interactions. EMBO J 13:2849–2861PubMedGoogle Scholar
  47. Langosch D, Heringa J (1998) Interaction of transmembrane helices by a knobs-into-holes packing characteristic of soluble coiled coils. Proteins 31:150–159PubMedCrossRefGoogle Scholar
  48. Lavigne P, Sonnichsen FD, Kay CM, Hodges RS, Lumb KJ, Kim PS (1996) Interhelical salt bridges, coiled coil stability, and specificity of dimerization. Science 271:1136–1138PubMedCrossRefGoogle Scholar
  49. Li F, Pincet F, Perez E, Eng WS, Melia TJ, Rothman JE, Tareste D (2007) Energetics and dynamics of SNAREpin folding across lipid bilayers. Nat Struct Mol Biol 14:890–896PubMedCrossRefGoogle Scholar
  50. Lim EC, Seet RC (2007) Botulinum toxin, Quo Vadis? Med Hypotheses 69:718–723PubMedCrossRefGoogle Scholar
  51. Liu J, Rost B (2001) Comparing function and structure between entire proteomes. Protein Sci 10:1970–1979PubMedCrossRefGoogle Scholar
  52. Lumb KJ, Kim PS (1995) Measurement of interhelical electrostatic interactions in the GCN4 leucine zipper. Science 268:436–439PubMedCrossRefGoogle Scholar
  53. Maiato H, DeLuca J, Salmon ED, Earnshaw WC (2004) The dynamic kinetochore–microtubule interface. J Cell Sci 117:5461–5477PubMedCrossRefGoogle Scholar
  54. Martínez-Carbonero L (2004) Discontinuation of the clinical development of fusion inhibitor T1249. AIDS Rev 6:61Google Scholar
  55. McLachlan AD, Stewart M (1975) Tropomyosin coiled coil interactions: evidence for an unstaggered structure. J Mol Biol 98:293–304PubMedCrossRefGoogle Scholar
  56. Newman JR, Keating AE (2003) Comprehensive identification of human bZIP interactions with coiled coil arrays. Science 300:2097–2101PubMedCrossRefGoogle Scholar
  57. O’Shea EK, Rutkowski R, Kim PS (1989) Preferential heterodimer formation by isolated leucine zippers from fos and jun. Science 245:646–648PubMedCrossRefGoogle Scholar
  58. O’Shea EK, Klemm JD, Kim PS, Alber T (1991) X-ray structure of the GCN4 leucine zipper, a two-stranded, parallel coiled coil. Science 254:539–544PubMedCrossRefGoogle Scholar
  59. O’Shea EK, Rutkowski R, Kim PS (1992) Mechanism of specificity in the Fos-Jun oncoprotein heterodimer. Cell 68:699–708PubMedCrossRefGoogle Scholar
  60. Otaka A, Nakamura M, Nameki D, Kodama E, Uchiyama S, Nakamura S, Nakano H, Tamamura H, Kobayashi Y, Matsuoka M, Fujii N (2002) Remodeling of gp41–C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells. Angew Chem Int Ed 41:2937–2940CrossRefGoogle Scholar
  61. Petka WA, Harden J L, McGrath KP, Wirtz D, Tirrell DA (1998) Reversible hydrogels from self-assembling artificial proteins. Science 281:389–392PubMedCrossRefGoogle Scholar
  62. Portwich M, Keller S, Strauss HM, Mahrenholz CC, Kramer A, Kretzschmar I, Volkmer R (2007). A network of coiled-coil associations derived from synthetic GCN4 leucine-zipper arrays. Angew Chem Int Ed 46:1654–1657CrossRefGoogle Scholar
  63. Potekhin SA, Medvedkin VN, Kashparov IA, Venyaminov SY (1994) Synthesis and properties of the peptide corresponding to the mutant form of the leucine zipper of the transcriptional activator GCN4 from yeast. Protein Eng 7:1097–1101PubMedCrossRefGoogle Scholar
  64. Schibli DJ, Weissenhorn W (2004) class I and class II viral fusion protein structures reveal similar principles in membrane fusion. Mol Membr Biol 21:361–371PubMedCrossRefGoogle Scholar
  65. Schuette CG, Hatsuzawa K, Margittai M, Stein A, Riedel D, Küster P, König M, Seidel C, Jahn R (2004) Determinants of liposome fusion mediated by synaptic SNARE proteins. Proc Natl Acad Sci USA 101:2858–2863PubMedCrossRefGoogle Scholar
  66. Sieber JJ, Willig KI, Heintzmann R, Hell SW, Lang T (2006) The SNARE motif is essential for the formation of syntaxin clusters in the plasma membrane. Biophys J 90:2843–2851PubMedCrossRefGoogle Scholar
  67. Sieber JJ, Willig KI, Kutzner C, Gerding-Reimers C, Harke B, Donnert G, Rammner B, Eggeling C, Hell SW, Grubmüller H, Lang T (2007) Anatomy and dynamics of a supramolecular membrane protein cluster. Science 317:1072–1076PubMedCrossRefGoogle Scholar
  68. Skehel JJ, Wiley DJ (2000) Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69:531–569PubMedCrossRefGoogle Scholar
  69. Sodek J, Hodges RS, Smillie LB, Jurasek L (1972) Amino-acid sequence of rabbit skeletal tropomyosin and its coiled-coil structure. Proc Natl Acad Sci USA 69:3800–3804PubMedCrossRefGoogle Scholar
  70. Söllner T, Whiteheart SW, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE (1993) SNAP receptors implicated in vesicle targeting and fusion. Nature 362:318–324PubMedCrossRefGoogle Scholar
  71. Stein A, Radhakrishnan A, Riedel D, Fasshauer D, Jahn R (2007) Synaptotagmin activates membrane fusion through a Ca2+-dependent trans interaction with phospholipids. Nat Struct Mol Biol 14:904–911PubMedCrossRefGoogle Scholar
  72. Steinert PM (1993) Structure, function, and dynamics of keratin intermediate filaments. J Invest Dermatol 100:729–734PubMedCrossRefGoogle Scholar
  73. Sutton RB, Fasshauer D, Jahn R, Brünger AT (1998) Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution. Nature 395:347–353PubMedCrossRefGoogle Scholar
  74. Tan K, Liu, J, Wang J-H, Shen S, Lu M (1997) Atomic structure of a thermostable subdomain of HIV-1 gp41. Proc Natl Acad Sci USA 94:12303–12308PubMedCrossRefGoogle Scholar
  75. Vinson CR, Sigler PB, McKnight SL (1989) Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science 246:911–916PubMedCrossRefGoogle Scholar
  76. Weber T, Zemelman BV, McNew JA, Westermann B, Gmachl M, Parlati F, Söllner TH, Rothman JE (1998) SNAREpins: minimal machinery for membrane fusion. Cell 92:759–772PubMedCrossRefGoogle Scholar
  77. Wei RR, Sorger PK, Harrison SC (2005) Molecular organization of the Ndc80 complex, an essential kinetochore component. Proc Natl Acad Sci USA 102:5363–5367PubMedCrossRefGoogle Scholar
  78. Wei RR, Schnell JR, Larsen NA, Sorger PK, Chou JJ, Harrison SC (2006) Structure of a central component of the yeast kinetochore: the Spc24p/Spc25p globular domain. Structure 14:1003–1009PubMedCrossRefGoogle Scholar
  79. Wei RR, Al-Bassam J, Harrison SC (2007) The Ndc80/HEC1 complex is a contact point for kinetochore–microtubule attachment. Nat Struct Mol Biol 14:54–59PubMedCrossRefGoogle Scholar
  80. Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC (1997) Atomic structure of the ectodomain from HIV-1 gp41. Nature 387:426–430PubMedCrossRefGoogle Scholar
  81. Weissenhorn W, Hinz A, Gaudin Y (2007) Virus membrane fusion. FEBS Lett 581:2150–2155PubMedCrossRefGoogle Scholar
  82. Wharton SA, Skehel JJ, Wiley DC (1986) Studies of influenza haemagglutinin-mediated membrane fusion. Virology 149:27–35PubMedCrossRefGoogle Scholar
  83. Wigge PA, Kilmartin JV (2001) The Ndc80p complex from Saccharomyces cerevisiae contains conserved centromere components and has a function in chromosome segregation. J Cell Biol 152:349–360PubMedCrossRefGoogle Scholar
  84. Wild C, Oas T, McDanal CB, Bolognesi D, Matthews T (1992) A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition. Proc Natl Acad Sci USA 89:10537–10541PubMedCrossRefGoogle Scholar
  85. Wild C, Shugars DC, Greenwell TK, McDanal CB, Matthews TJ (1994) Peptides corresponding to a predictive α-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci USA 91:9770–9774PubMedCrossRefGoogle Scholar
  86. Wilson IA, Skehel JJ, Wiley DC (1981) Structure of the haemeagglutinin membrane glycoprotein of influenza virus at 3 Å resolution. Nature 289:366–373PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • H. M. Strauss
    • 1
  • S. Keller
    • 2
  1. 1.NanolyticsGesellschaft für Kolloidanalytik mbHPotsdamGermany
  2. 2.Leibniz Institute of Molecular Pharmacology FMPBerlinGermany

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