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Chemical Synthesis and Biological Function of Lipidated Proteins

Part of the Topics in Current Chemistry book series (TOPCURRCHEM,volume 362)

Abstract

Lipidated proteins play a key role in many essential biological processes in eukaryotic cells, including signal transduction, membrane trafficking, immune response and pathology. The investigation of the function of lipidated proteins requires access to a reasonable amount of homogenous lipid-modified proteins with defined structures and functional groups. Chemical approaches have provided useful tools to perform such studies. In this review we summarize synthetic methods of lipidated peptides and developments in the chemoselective ligation for the production of lipidated proteins. We introduce the biology of lipidated proteins and highlight the application of synthetic lipidated proteins to tackle important biological questions.

Keywords

  • Click ligation
  • Diels–Alder ligation
  • Expressed protein ligation
  • GPI anchor
  • MIC ligation
  • Peptide synthesis
  • Protein lipidation
  • Rab
  • Ras
  • Rheb
  • Sortase-mediated protein ligation

$Both authors contributed equally to this work.

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References

  1. Resh MD (2006) Nat Chem Biol 2:584–590

    CAS  Google Scholar 

  2. Carr SA, Biemann K, Shoji S, Parmelee DC, Titani K (1982) Proc Natl Acad Sci U S A 79:6128–6131

    CAS  Google Scholar 

  3. Aitken A, Cohen P, Santikarn S, Williams DH, Calder AG, Smith A, Klee CB (1982) FEBS Lett 150:314–318

    CAS  Google Scholar 

  4. Farazi TA, Waksman G, Gordon JI (2001) J Biol Chem 276:39501–39504

    CAS  Google Scholar 

  5. Gheysen D, Jacobs E, de Foresta F, Thiriart C, Francotte M, Thines D, De Wilde M (1989) Cell 59:103–112

    CAS  Google Scholar 

  6. Liu Y, Kahn RA, Prestegard JH (2009) Structure 17:79–87

    CAS  Google Scholar 

  7. Hutagalung AH, Novick PJ (2011) Physiol Rev 91:119–149

    CAS  Google Scholar 

  8. Stenmark H (2009) Nat Rev Mol Cell Biol 10:513–525

    CAS  Google Scholar 

  9. Amor JC, Harrison DH, Kahn RA, Ringe D (1994) Nature 372:704–708

    CAS  Google Scholar 

  10. Goldberg J (1998) Cell 95:237–248

    CAS  Google Scholar 

  11. Maurer-Stroh S, Eisenhaber F (2004) Trends Microbiol 12:178–185

    CAS  Google Scholar 

  12. Pal R, Reitz MS Jr, Tschachler E, Gallo RC, Sarngadharan MG, Veronese FD (1990) AIDS Res Hum Retroviruses 6:721–730

    CAS  Google Scholar 

  13. Provitera P, El-Maghrabi R, Scarlata S (2006) Biophys Chem 119:23–32

    CAS  Google Scholar 

  14. Casey PJ (1995) Science 268:221–225

    CAS  Google Scholar 

  15. Resh MD (1999) Biochim Biophys Acta 1451:1–16

    CAS  Google Scholar 

  16. Kang R, Wan J, Arstikaitis P, Takahashi H, Huang K, Bailey AO, Thompson JX, Roth AF, Drisdel RC, Mastro R, Green WN, Yates JR 3rd, Davis NG, El-Husseini A (2008) Nature 456:904–909

    CAS  Google Scholar 

  17. Wedegaertner PB, Bourne HR (1994) Cell 77:1063–1070

    CAS  Google Scholar 

  18. Rocks O, Peyker A, Kahms M, Verveer PJ, Koerner C, Lumbierres M, Kuhlmann J, Waldmann H, Wittinghofer A, Bastiaens PI (2005) Science 307:1746–1752

    CAS  Google Scholar 

  19. Tu Y, Wang J, Ross EM (1997) Science 278:1132–1135

    CAS  Google Scholar 

  20. Rocks O, Gerauer M, Vartak N, Koch S, Huang ZP, Pechlivanis M, Kuhlmann J, Brunsveld L, Chandra A, Ellinger B, Waldmann H, Bastiaens PI (2010) Cell 141:458–471

    CAS  Google Scholar 

  21. Chandra A, Grecco HE, Pisupati V, Perera D, Cassidy L, Skoulidis F, Ismail SA, Hedberg C, Hanzal-Bayer M, Venkitaraman AR, Wittinghofer A, Bastiaens PI (2012) Nat Cell Biol 14:148–158

    CAS  Google Scholar 

  22. Zhang FL, Casey PJ (1996) Annu Rev Biochem 65:241–269

    CAS  Google Scholar 

  23. Casey PJ, Seabra MC (1996) J Biol Chem 271:5289–5292

    CAS  Google Scholar 

  24. Maurer-Stroh S, Washietl S, Eisenhaber F (2003) Genome Biol 4:212

    Google Scholar 

  25. Nguyen UT, Goody RS, Alexandrov K (2010) Chembiochem 11:1194–1201

    CAS  Google Scholar 

  26. Clarke S (1992) Annu Rev Biochem 61:355–386

    CAS  Google Scholar 

  27. Wu YW, Goody RS, Abagyan R, Alexandrov K (2009) J Biol Chem 284:13185–13192

    CAS  Google Scholar 

  28. Li F, Yi L, Zhao L, Itzen A, Goody RS, Wu YW (2014) Proc Natl Acad Sci U S A 111:2572–2577

    CAS  Google Scholar 

  29. Rak A, Pylypenko O, Durek T, Watzke A, Kushnir S, Brunsveld L, Waldmann H, Goody RS, Alexandrov K (2003) Science 302:646–650

    CAS  Google Scholar 

  30. Wu YW, Tan KT, Waldmann H, Goody RS, Alexandrov K (2007) Proc Natl Acad Sci U S A 104:12294–12299

    CAS  Google Scholar 

  31. Yu S, Guo Z, Johnson C, Gu G, Wu Q (2013) Curr Opin Chem Biol 17:1006–1013

    CAS  Google Scholar 

  32. Tsai YH, Liu X, Seeberger PH (2012) Angew Chem Int Ed Engl 51:11438–11456

    CAS  Google Scholar 

  33. Paulick MG, Bertozzi CR (2008) Biochemistry 47:6991–7000

    CAS  Google Scholar 

  34. Levental I, Grzybek M, Simons K (2010) Biochemistry 49:6305–6316

    CAS  Google Scholar 

  35. Nosjean O, Briolay A, Roux B (1997) Biochim Biophys Acta 1331:153–186

    CAS  Google Scholar 

  36. Ishihara A, Hou Y, Jacobson K (1987) Proc Natl Acad Sci U S A 84:1290–1293

    CAS  Google Scholar 

  37. Schofield L, McConville MJ, Hansen D, Campbell AS, Fraser-Reid B, Grusby MJ, Tachado SD (1999) Science 283:225–229

    CAS  Google Scholar 

  38. Weissmann C (2004) Nat Rev Microbiol 2:861–871

    CAS  Google Scholar 

  39. Chesebro B, Trifilo M, Race R, Meade-White K, Teng C, LaCasse R, Raymond L, Favara C, Baron G, Priola S, Caughey B, Masliah E, Oldstone M (2005) Science 308:1435–1439

    CAS  Google Scholar 

  40. Zuegg J, Gready JE (2000) Glycobiology 10:959–974

    CAS  Google Scholar 

  41. Hall TM, Porter JA, Young KE, Koonin EV, Beachy PA, Leahy DJ (1997) Cell 91:85–97

    CAS  Google Scholar 

  42. Buglino JA, Resh MD (2008) J Biol Chem 283:22076–22088

    CAS  Google Scholar 

  43. Guerrero I, Chiang C (2007) Trends Cell Biol 17:1–5

    CAS  Google Scholar 

  44. Mizushima N, Yoshimori T, Ohsumi Y (2011) Annu Rev Cell Dev Biol 27:107–132

    CAS  Google Scholar 

  45. Feng Y, He D, Yao Z, Klionsky DJ (2014) Cell Res 24:24–41

    CAS  Google Scholar 

  46. Hackenberger CPR, Schwarzer D (2008) Angew Chem Int Ed Engl 47:10030–10074

    CAS  Google Scholar 

  47. Brunsveld L, Kuhlmann J, Alexandrov K, Wittinghofer A, Goody RS, Waldmann H (2006) Angew Chem Int Ed Engl 45:6622–6646

    CAS  Google Scholar 

  48. Gerauer M, Koch S, Brunsveld L, Waldmann H (2009) Lipidated peptide synthesis. In: Begley TP (ed) Wiley encyclopedia of chemical biology, vol 2. Wiley, New Jersey, pp 520–530

    Google Scholar 

  49. Görmer K, Waldmann H, Brunsveld L (2010) Lipidation of peptides and proteins. In: Mander L, Lui H-W (eds) Comprehensive natural products II: chemistry and biology, vol 5. Elsevier, Oxford, pp 531–585

    Google Scholar 

  50. Lumbierres M, Palomo JM, Kragol G, Roehrs S, Muller O, Waldmann H (2005) Chemistry 11:7405–7415

    CAS  Google Scholar 

  51. Kadereit D, Deck P, Heinemann I, Waldmann H (2001) Chemistry 7:1184–1193

    CAS  Google Scholar 

  52. Kadereit D, Waldmann H (2000) Chembiochem 1:200–203

    CAS  Google Scholar 

  53. Brunsveld L, Watzke A, Durek T, Alexandrov K, Goody RS, Waldmann H (2005) Chemistry 11:2756–2772

    CAS  Google Scholar 

  54. Durek T, Alexandrov K, Goody RS, Hildebrand A, Heinemann I, Waldmann H (2004) J Am Chem Soc 126:16368–16378

    CAS  Google Scholar 

  55. Millington CR, Quarrell R, Lowe G (1998) Tetrahedron Lett 39:7201–7204

    CAS  Google Scholar 

  56. Ludolph B, Eisele F, Waldmann H (2002) J Am Chem Soc 124:5954–5955

    CAS  Google Scholar 

  57. Rosenbaum C, Waldmann H (2001) Tetrahedron Lett 42:5677–5680

    CAS  Google Scholar 

  58. Backes BJ, Ellman JA (1999) J Org Chem 64:2322–2330

    CAS  Google Scholar 

  59. Triola G, Gerauer M, Gormer K, Brunsveld L, Waldmann H (2010) Chemistry 16:9585–9591

    CAS  Google Scholar 

  60. Palomo JM, Lumbierres M, Waldmann H (2006) Angew Chem Int Ed Engl 45:477–481

    CAS  Google Scholar 

  61. Chen YX, Koch S, Uhlenbrock K, Weise K, Das D, Gremer L, Brunsveld L, Wittinghofer A, Winter R, Triola G, Waldmann H (2010) Angew Chem Int Ed Engl 49:6090–6095

    CAS  Google Scholar 

  62. Yang A, Li Y, Pantoom S, Triola G, Wu YW (2013) Chembiochem 14:1296–1300

    CAS  Google Scholar 

  63. Grogan MJ, Kaizuka Y, Conrad RM, Groves JT, Bertozzi CR (2005) J Am Chem Soc 127:14383–14387

    CAS  Google Scholar 

  64. Huang YC, Li YM, Chen Y, Pan M, Li YT, Yu L, Guo QX, Liu L (2013) Angew Chem Int Ed Engl 52:4858–4862

    Google Scholar 

  65. Peters C, Wolf A, Wagner M, Kuhlmann J, Waldmann H (2004) Proc Natl Acad Sci U S A 101:8531–8536

    CAS  Google Scholar 

  66. Goody RS, Alexandrov K, Engelhard M (2002) Chembiochem 3:399–403

    CAS  Google Scholar 

  67. Kho Y, Kim SC, Jiang C, Barma D, Kwon SW, Cheng J, Jaunbergs J, Weinbaum C, Tamanoi F, Falck J, Zhao Y (2004) Proc Natl Acad Sci U S A 101:12479–12484

    CAS  Google Scholar 

  68. Nguyen UT, Cramer J, Gomis J, Reents R, Gutierrez-Rodriguez M, Goody RS, Alexandrov K, Waldmann H (2007) Chembiochem 8:408–423

    CAS  Google Scholar 

  69. Duckworth BP, Zhang Z, Hosokawa A, Distefano MD (2007) Chembiochem 8:98–105

    CAS  Google Scholar 

  70. Dursina B, Reents R, Delon C, Wu Y, Kulharia M, Thutewohl M, Veligodsky A, Kalinin A, Evstifeev V, Ciobanu D, Szedlacsek SE, Waldmann H, Goody RS, Alexandrov K (2006) J Am Chem Soc 128:2822–2835

    CAS  Google Scholar 

  71. Nguyen UT, Guo Z, Delon C, Wu Y, Deraeve C, Franzel B, Bon RS, Blankenfeldt W, Goody RS, Waldmann H, Wolters D, Alexandrov K (2009) Nat Chem Biol 5:227–235

    CAS  Google Scholar 

  72. Berry AF, Heal WP, Tarafder AK, Tolmachova T, Baron RA, Seabra MC, Tate EW (2010) Chembiochem 11:771–773

    CAS  Google Scholar 

  73. Yi L, Abootorabi M, Wu YW (2011) Chembiochem 12:2413–2417

    CAS  Google Scholar 

  74. Paulick MG, Wise AR, Forstner MB, Groves JT, Bertozzi CR (2007) J Am Chem Soc 129:11543–11550

    CAS  Google Scholar 

  75. Alexandrov K, Heinemann I, Durek T, Sidorovitch V, Goody RS, Waldmann H (2002) J Am Chem Soc 124:5648–5649

    CAS  Google Scholar 

  76. Olschewski D, Seidel R, Miesbauer M, Rambold AS, Oesterhelt D, Winklhofer KF, Tatzelt J, Engelhard M, Becker CF (2007) Chem Biol 14:994–1006

    CAS  Google Scholar 

  77. Antos JM, Miller GM, Grotenbreg GM, Ploegh HL (2008) J Am Chem Soc 130:16338–16343

    CAS  Google Scholar 

  78. Reents R, Wagner M, Kuhlmann J, Waldmann H (2004) Angew Chem Int Ed Engl 43:2711–2714

    CAS  Google Scholar 

  79. Chu NK, Becker CF (2009) Methods Enzymol 462:177–193

    CAS  Google Scholar 

  80. Dawson PE, Muir TW, Clark-Lewis I, Kent SB (1994) Science 266:776–779

    CAS  Google Scholar 

  81. Dawson PE, Kent SB (2000) Annu Rev Biochem 69:923–960

    CAS  Google Scholar 

  82. Muir TW (2003) Annu Rev Biochem 72:249–289

    CAS  Google Scholar 

  83. Muir TW, Sondhi D, Cole PA (1998) Proc Natl Acad Sci U S A 95:6705–6710

    CAS  Google Scholar 

  84. Siman P, Brik A (2012) Org Biomol Chem 10:5684–5697

    CAS  Google Scholar 

  85. Vila-Perello M, Muir TW (2010) Cell 143:191–200

    CAS  Google Scholar 

  86. Kuhn K, Owen DJ, Bader B, Wittinghofer A, Kuhlmann J, Waldmann H (2001) J Am Chem Soc 123:1023–1035

    CAS  Google Scholar 

  87. Wu YW, Oesterlin LK, Tan KT, Waldmann H, Alexandrov K, Goody RS (2010) Nat Chem Biol 6:534–540

    CAS  Google Scholar 

  88. Paulick MG, Forstner MB, Groves JT, Bertozzi CR (2007) Proc Natl Acad Sci U S A 104:20332–20337

    CAS  Google Scholar 

  89. Becker CF, Liu X, Olschewski D, Castelli R, Seidel R, Seeberger PH (2008) Angew Chem Int Ed Engl 47:8215–8219

    CAS  Google Scholar 

  90. Johnson EC, Kent SB (2006) J Am Chem Soc 128:6640–6646

    CAS  Google Scholar 

  91. Janosch S, Nicolini C, Ludolph B, Peters C, Völkert M, Hazlet TL, Gratton E, Waldmann H, Winter R (2004) J Am Chem Soc 126:7496–7503

    CAS  Google Scholar 

  92. Reents R, Wagner M, Schlummer S, Kuhlmann J, Waldmann H (2005) Chembiochem 6:86–94

    CAS  Google Scholar 

  93. Bader B, Kuhn K, Owen DJ, Waldmann H, Wittinghofer A, Kuhlmann J (2000) Nature 403:223–226

    CAS  Google Scholar 

  94. de Araujo AD, Palomo JM, Cramer J, Kohn M, Schroder H, Wacker R, Niemeyer C, Alexandrov K, Waldmann H (2005) Angew Chem Int Ed Engl 45:296–301

    Google Scholar 

  95. de Araujo AD, Palomo JM, Cramer J, Seitz O, Alexandrov K, Waldmann H (2006) Chemistry 12:6095–6109

    Google Scholar 

  96. Kolb HC, Finn MG, Sharpless KB (2001) Angew Chem Int Ed Engl 40:2004–2021

    CAS  Google Scholar 

  97. Huang X, Aulabaugh A, Ding W, Kapoor B, Alksne L, Tabei K, Ellestad G (2003) Biochemistry 42:11307–11315

    CAS  Google Scholar 

  98. Frankel BA, Kruger RG, Robinson DE, Kelleher NL, McCafferty DG (2005) Biochemistry 44:11188–11200

    CAS  Google Scholar 

  99. Dementiev A (2012) Protein Expr Purif 84:86–93

    CAS  Google Scholar 

  100. Wu Z, Guo X, Gao J, Guo Z (2013) Chem Commun (Camb) 49:11689–11691

    CAS  Google Scholar 

  101. de Almeida RF, Fedorov A, Prieto M (2003) Biophys J 85:2406–2416

    Google Scholar 

  102. Nicolini C, Baranski J, Schlummer S, Palomo J, Lumbierres-Burgues M, Kahms M, Kuhlmann J, Sanchez S, Gratton E, Waldmann H, Winter R (2006) J Am Chem Soc 128:192–201

    CAS  Google Scholar 

  103. Weise K, Triola G, Brunsveld L, Waldmann H, Winter R (2009) J Am Chem Soc 131:1557–1564

    CAS  Google Scholar 

  104. Weise K, Kapoor S, Denter C, Nikolaus J, Opitz N, Koch S, Triola G, Herrmann A, Waldmann H, Winter R (2011) J Am Chem Soc 133:880–887

    CAS  Google Scholar 

  105. Kapoor S, Triola G, Vetter IR, Erlkamp M, Waldmann H, Winter R (2012) Proc Natl Acad Sci U S A 109:460–465

    CAS  Google Scholar 

  106. Hanzal-Bayer M, Renault L, Roversi P, Wittinghofer A, Hillig RC (2002) EMBO J 21:2095–2106

    CAS  Google Scholar 

  107. Ismail SA, Chen YX, Rusinova A, Chandra A, Bierbaum M, Gremer L, Triola G, Waldmann H, Bastiaens PI, Wittinghofer A (2011) Nat Chem Biol 7:942–949

    CAS  Google Scholar 

  108. Nancy V, Callebaut I, El Marjou A, de Gunzburg J (2002) J Biol Chem 277:15076–15084

    CAS  Google Scholar 

  109. Linari M, Hanzal-Bayer M, Becker J (1999) FEBS Lett 458:55–59

    CAS  Google Scholar 

  110. Veltel S, Kravchenko A, Ismail S, Wittinghofer A (2008) FEBS Lett 582:2501–2507

    CAS  Google Scholar 

  111. Groves JT, Dustin ML (2003) J Immunol Methods 278:19–32

    CAS  Google Scholar 

  112. Sletten EM, Bertozzi CR (2009) Angew Chem Int Ed Engl 48:6974–6998

    CAS  Google Scholar 

  113. Ramil CP, Lin Q (2013) Chem Commun (Camb) 49:11007–11022

    CAS  Google Scholar 

  114. Wu YW, Goody RS (2010) J Pept Sci 16:514–523

    CAS  Google Scholar 

  115. Takaoka Y, Ojida A, Hamachi I (2013) Angew Chem Int Ed Engl 52:4088–4106

    CAS  Google Scholar 

  116. Lang K, Chin JW (2014) Chem Rev 114:4764–4806

    CAS  Google Scholar 

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Yang, A., Zhao, L., Wu, YW. (2014). Chemical Synthesis and Biological Function of Lipidated Proteins. In: Liu, L. (eds) Protein Ligation and Total Synthesis I. Topics in Current Chemistry, vol 362. Springer, Cham. https://doi.org/10.1007/128_2014_582

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