Abstract
N-myristoylation is the attachment of a 14-carbon fatty acid, myristate, onto the N-terminal glycine residue of target proteins, catalysed by N-myristoyltransferase (NMT), a ubiquitous and essential enzyme in eukaryotes. Many of the target proteins of NMT are crucial components of signalling pathways, and myristoylation typically promotes membrane binding that is essential for proper protein localisation or biological function. NMT is a validated therapeutic target in opportunistic infections of humans by fungi or parasitic protozoa. Additionally, NMT is implicated in carcinogenesis, particularly colon cancer, where there is evidence for its upregulation in the early stages of tumour formation. However, the study of myristoylation in all organisms has until recently been hindered by a lack of techniques for detection and identification of myristoylated proteins. Here we introduce the chemistry and biology of N-myristoylation and NMT, and discuss new developments in chemical proteomic technologies that are meeting the challenge of studying this important co-translational modification in living systems.
Similar content being viewed by others
References
Woycechowsky KJ, Raines RT (2000) Curr Opin Chem Biol 4:533–539
Ehrmann M, Clausen T (2004) Annu Rev Genet 38:709–724
Giglione C, Boularot A, Meinnel T (2004) Cell Mol Life Sci 61:1455–1474
Hershko A, Ciechanover A (1998) Annu Rev Biochem 67:425–479
Zhao J (2007) Cell Mol Life Sci 64:3017–3033
Cheung WL, Briggs SD, Allis CD (2000) Curr Opin Cell Biol 12:326–333
Karakozova M, Kozak M, Wong CC, Bailey AO, Yates JR 3rd, Mogilner A, Zebroski H, Kashina A (2006) Science 313:192–196
Farazi TA, Waksman G, Gordon JI (2001) J Biol Chem 276:39501–39504
Buglino JA, Resh MD (2008) J Biol Chem 283:22076–22088
Paik WK, Paik DC, Kim S (2007) Trends Biochem Sci 32:146–152
Cohen P (2000) Trends Biochem Sci 25:596–601
Spiro RG (2002) Glycobiology 12:43R–56R
Resh MD (2006) Nat Chem Biol 2:584–590
Resh MD (2004) Subcell Biochem 37:217–232
Poole LB, Karplus PA, Claiborne A (2004) Annu Rev Pharmacol Toxicol 44:325–347
Gordon JI, Duronio RJ, Rudnick DA, Adams SP, Gokel GW (1991) J Biol Chem 266:8647–8650
Boutin JA (1997) Cell Signal 9:15–35
Wilcox C, Hu JS, Olson EN (1987) Science 238:1275–1278
Deichaite I, Casson LP, Ling HP, Resh MD (1988) Mol Cell Biol 8:4295–4301
Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ (2000) Science 290:1761–1765
Resh MD (1999) Biochim Biophys Acta-Mol Cell Res 1451:1–16
Towler DA, Adams SP, Eubanks SR, Towery DS, Jackson-Machelski E, Glaser L, Gordon JI (1987) Proc Natl Acad Sci U S A 84:2708–2712
Lodge JK, Johnson RL, Weinberg RA, Gordon JI (1994) J Biol Chem 269:2996–3009
Shaw BD, Momany C, Momany M (2002) Eukaryot Cell 1:241–248
Gunaratne RS, Sajid M, Ling IT, Tripathi R, Pachebat JA, Holder AA (2000) Biochem J 348(Pt 2):459–463
Panethymitaki C, Bowyer PW, Price HP, Leatherbarrow RJ, Brown KA, Smith DF (2006) Biochem J 396:277–285
Ntwasa M, Aapies S, Schiffmann DA, Gay NJ (2001) Exp Cell Res 262:134–144
Boisson B, Giglione C, Meinnel T (2003) J Biol Chem 278:43418–43429
Duronio RJ, Towler DA, Heuckeroth RO, Gordon JI (1989) Science 243:796–800
Weinberg RA, McWherter CA, Freeman SK, Wood DC, Gordon JI, Lee SC (1995) Mol Microbiol 16:241–250
Lodge JK, Jackson-Machelski E, Toffaletti DL, Perfect JR, Gordon JI (1994) Proc Natl Acad Sci U S A 91:12008–12012
Price HP, Menon MR, Panethymitaki C, Goulding D, McKean PG, Smith DF (2003) J Biol Chem 278:7206–7214
Yang SH, Shrivastav A, Kosinski C, Sharma RK, Chen M-H, Berthiaume LG, Peters LL, Chuang P-T, Young SG, Bergo MO (2005) J Biol Chem 280:18990–18995
Rudnick DA, McWherter CA, Rocque WJ, Lennon PJ, Getman DP, Gordon JI (1991) J Biol Chem 266:9732–9739
Rocque WJ, Mcwherter CA, Wood DC, Gordon JI (1993) J Biol Chem 268:9964–9971
Peseckis SM, Resh MD (1994) J Biol Chem 269:30888–30892
Zhang L, Jackson-Machelski E, Gordon JI (1996) J Biol Chem 271:33131–33140
Weston SA, Camble R, Colls J, Rosenbrock G, Taylor I, Egerton M, Tucker AD, Tunnicliffe A, Mistry A, Mancia F, de la Fortelle E, Irwin J, Bricogne G, Pauptit RA (1998) Nat Struct Biol 5:213–221
Bhatnagar RS, Futterer K, Farazi TA, Korolev S, Murray CL, Jackson-Machelski E, Gokel GW, Gordon JI, Waksman G (1998) Nat Struct Mol Biol 5:1091–1097
Farazi TA, Waksman G, Gordon JI (2001) Biochem 40:6335–6343
Sogabe S, Masubuchi M, Sakata K, Fukami TA, Morikami K, Shiratori Y, Ebiike H, Kawasaki K, Aoki Y, Shimma N, D’Arcy A, Winkler FK, Banner DW, Ohtsuka T (2002) Chem Biol 9:1119–1128
Wu J, Tao Y, Zhang M, Howard MH, Gutteridge S, Ding J (2007) J Biol Chem 282:22185–22194
Rioux V, Legrand P (2007) Curr Opin Clin Nutr Metab Care 10:752–758
Farazi TA, Manchester JK, Waksman G, Gordon JI (2001) Biochem 40:9177–9186
Farazi TA, Manchester JK, Gordon JI (2000) Biochem 39:15807–15816
Heuckeroth RO, Glaser L, Gordon JI (1988) Proc Natl Acad Sci U S A 85:8795–8799
Heuckeroth RO, Jackson-Machelski E, Adams SP, Kishore NS, Huhn M, Katoh A, Lu T, Gokel GW, Gordon JI (1990) J Lipid Res 31:1121–1129
Kishore NS, Lu TB, Knoll LJ, Katoh A, Rudnick DA, Mehta PP, Devadas B, Huhn M, Atwood JL, Adams SP et al (1991) J Biol Chem 266:8835–8855
Devadas B, Lu T, Katoh A, Kishore NS, Wade AC, Mehta PP, Rudnick DA, Bryant ML, Adams SP, Li Q et al (1992) J Biol Chem 267:7224–7239
Lu T, Li Q, Katoh A, Hernandez J, Duffin K, Jackson-Machelski E, Knoll LJ, Gokel GW, Gordon JI (1994) J Biol Chem 269:5346–5357
Pasha MK, Selvakumar P, Ashakumary L, Qureshi M, Guziec FS Jr, Dimmock JR, Felsted RL, Glover CJ, Sharma RK (2004) Int J Mol Med 13:557–563
Bhatnagar RS, Schall OF, Jackson-Machelski E, Sikorski JA, Devadas B, Gokel GW, Gordon JI (1997) Biochem 36:6700–6708
Kishore NS, Wood DC, Mehta PP, Wade AC, Lu T, Gokel GW, Gordon JI (1993) J Biol Chem 268:4889–4902
Heuckeroth RO, Towler DA, Adams SP, Glaser L, Gordon JI (1988) J Biol Chem 263:2127–2133
Rudnick DA, Lu TB, Jacksonmachelski E, Hernandez JC, Li Q, Gokel GW, Gordon JI (1992) Proc Natl Acad Sci U S A 89:10507–10511
Bhatnagar RS, Jackson-Machelski E, McWherter CA, Gordon JI (1994) J Biol Chem 269:11045–11053
Towler DA, Eubanks SR, Towery DS, Adams SP, Glaser L (1987) J Biol Chem 262:1030–1036
Towler DA, Gordon JI, Adams SP, Glaser L (1988) Annu Rev Biochem 57:69–97
Maurer-Stroh S, Eisenhaber B, Eisenhaber F (2002) J Mol Biol 317:523–540
Maurer-Stroh S, Eisenhaber B, Eisenhaber F (2002) J Mol Biol 317:541–557
Raju RV, Magnuson BA, Sharma RK (1995) Mol Cell Biochem 149–150:191–202
Duronio RJ, Rudnick DA, Adams SP, Towler DA, Gordon JI (1991) J Biol Chem 266:10498–10504
Giang DK, Cravatt BF (1998) J Biol Chem 273:6595–6598
Rioux V, Beauchamp E, Pedrono F, Daval S, Molle D, Catheline D, Legrand P (2006) Mol Cell Biochem 286:161–170
King MJ, Sharma RK (1992) Mol Cell Biochem 113:77–81
Glover CJ, Felsted RL (1995) J Biol Chem 270:23226–23233
McIlhinney RA, Young K, Egerton M, Camble R, White A, Soloviev M (1998) Biochem J 333(Pt 3):491–495
Glover CJ, Hartman KD, Felsted RL (1997) J Biol Chem 272:28680–28689
DeMar JC, Rundle DR, Wensel TG, Anderson RE (1999) Prog Lipid Res 38:49–89
Rundle DR, Rajala RVS, Anderson RE (2002) Exp Eye Res 75:87–97
Rundle DR, Rajala RV, Alvarez RA, Anderson RE (2004) Mol Vis 10:177–185
Johnson DR, Bhatnagar RS, Knoll LJ, Gordon JI (1994) Annu Rev Biochem 63:869–914
Peitzsch RM, McLaughlin S (1993) Biochem 32:10436–10443
Berthiaume L, Resh MD (1995) J Biol Chem 270:22399–22405
Das AK, Dasgupta B, Bhattacharya R, Basu J (1997) J Biol Chem 272:11021–11025
King MJ, Sharma RK (1993) Biochem J 291:635–639
King MJ, Sharma RK (1994) Mol Cell Biochem 141:79–86
Selvakumar P, Lakshmikuttyamma A, Pasha MK, King MJ, Olson DJH, Mori S, Ross ARS, Hayashi K, Dimmock JR, Sharma RK (2004) J Cell Biochem 92:573–578
McIlhinney RA, McGlone K (1990) Biochem J 271:681–685
Manenti S, Sorokine O, Van Dorsselaer A, Taniguchi H (1994) J Biol Chem 269:8309–8313
Braun T, McIlhinney RA, Vergeres G (2000) Biochimie 82:705–715
Raju RV, Kakkar R, Datla RS, Radhi J, Sharma RK (1998) Exp Cell Res 241:23–35
Selvakumar P, Smith-Windsor E, Bonham K, Sharma RK (2006) FEBS Lett 580:2021–2026
Raju RVS, Sharma RK (1996) Mol Cell Biochem 158:107–113
McIlhinney RA, Patel PB, McGlone K (1994) Eur J Biochem 222:137–146
Selvakumar P, Sharma RK (2006) Can J Physiol Pharmacol 84:707–712
Martinez A, Traverso JA, Valot B, Ferro M, Espagne C, Ephritikhine G, Zivy M, Giglione C, Meinnel T (2008) Proteomics 8:2809–2831
Braam B, Verhaar MC (2007) Curr Pharm Des 13:1727–1740
Maurer-Stroh S, Eisenhaber F (2004) Trends Microbiol 12:178–185
Zheng J, Knighton DR, Xuong NH, Taylor SS, Sowadski JM, Ten Eyck LF (1993) Protein Sci 2:1559–1573
Chow M, Newman JF, Filman D, Hogle JM, Rowlands DJ, Brown F (1987) Nature 327:482–486
Simons J, Rogove A, Moscufo N, Reynolds C, Chow M (1993) J Virol 67:1734–1738
Colombo S, Longhi R, Alcaro S, Ortuso F, Sprocati T, Flora A, Borgese N (2005) J Cell Biol 168:735–745
Cross FR, Garber EA, Pellman D, Hanafusa H (1984) Mol Cell Biol 4:1834–1842
Sigal CT, Zhou W, Buser CA, McLaughlin S, Resh MD (1994) Proc Natl Acad Sci U S A 91:12253–12257
Zhou W, Parent LJ, Wills JW, Resh MD (1994) J Virol 68:2556–2569
Swierczynski SL, Blackshear PJ (1996) J Biol Chem 271:23424–23430
Goldberg J (1998) Cell 95:237–248
McLaughlin S, Aderem A (1995) Trends Biochem Sci 20:272–276
Mishkind M (2001) Trends Cell Biol 11:191
Wyllie AH (1997) Br Med Bull 53:451–465
Simon GM, Dix MM, Cravatt BF (2009) ACS Chem Biol 4:401–408
Utsumi T, Sakurai N, Nakano K, Ishisaka R (2003) FEBS Lett 539:37–44
Sakurai N, Utsumi T (2006) J Biol Chem 281:14288–14295
Vilas GL, Corvi MM, Plummer GJ, Seime AM, Lambkin GR, Berthiaume LG (2006) Proc Natl Acad Sci U S A 103:6542–6547
Martin DD, Vilas GL, Prescher JA, Rajaiah G, Falck JR, Bertozzi CR, Berthiaume LG (2008) FASEB J 22:797–806
Ducker CE, Upson JJ, French KJ, Smith CD (2005) Mol Cancer Res 3:463–476
Felsted RL, Glover CJ, Hartman K (1995) J Natl Cancer Inst 87:1571–1573
Owa T, Yoshino H, Yoshimatsu K, Nagasu T (2001) Curr Med Chem 8:1487–1503
Devadas B, Zupec ME, Freeman SK, Brown DL, Nagarajan S, Sikorski JA, McWherter CA, Getman DP, Gordon JI (1995) J Med Chem 38:1837–1840
Nagarajan SR, Devadas B, Zupec ME, Freeman SK, Brown DL, Lu HF, Mehta PP, Kishore NS, McWherter CA, Getman DP, Gordon JI, Sikorski JA (1997) J Med Chem 40:1422–1438
Lodge JK, Jackson-Machelski E, Higgins M, McWherter CA, Sikorski JA, Devadas B, Gordon JI (1998) J Biol Chem 273:12482–12491
Bowyer PW, Tate EW, Leatherbarrow RJ, Holder AA, Smith DF, Brown KA (2008) Chem Med Chem 3:402–408
Bowyer PW, Gunaratne RS, Grainger M, Withers-Martinez C, Wickramsinghe SR, Tate EW, Leatherbarrow RJ, Brown KA, Holder AA, Smith DF (2007) Biochem J 408:173–180
Furuishi K, Matsuoka H, Takama M, Takahashi I, Misumi S, Shoji S (1997) Biochem Biophys Res Commun 237:504–511
Seaton KE, Smith CD (2008) J Gen Virol 89:288–296
Takamune N, Gota K, Misumi S, Tanaka K, Okinaka S, Shoji S (2008) Microbes Infect 10:143–150
Hill BT, Skowronski J (2005) J Virol 79:1133–1141
Magnuson BA, Raju RVS, Moyana TN, Sharma RK (1995) J Natl Cancer Inst 87:1630–1635
Raju RVS, Moyana TN, Sharma RK (1997) Exp Cell Res 235:145–154
Rajala RV, Radhi JM, Kakkar R, Datla RS, Sharma RK (2000) Cancer 88:1992–1999
Shrivastav A, Sharma AR, Bajaj G, Charavaryamath C, Ezzat W, Spafford P, Gore-Hickman R, Singh B, Copete MA, Sharma RK (2007) Oncol Rep 18:93–97
Lu Y, Selvakumar P, Ali K, Shrivastav A, Bajaj G, Resch L, Griebel R, Fourney D, Meguro K, Sharma RK (2005) Neurochem Res 30:9–13
Clegg RA, Gordge PC, Miller WR (1999) Adv Enzyme Regul 39:175–203
Frame MC (2002) Biochim Biophys Acta 1602:114–130
Wilson LK, Luttrell DK, Parsons JT, Parsons SJ (1989) Mol Cell Biol 9:1536–1544
Engen JR, Wales TE, Hochrein JM, Meyn MA, Ozkan SB, Bahar I, Smithgall TE (2008) Cell Mol Life Sci 65:3058–3073
Bagrodia S, Taylor SJ, Shalloway D (1993) Mol Cell Biol 13:1464–1470
Talamonti MS, Roh MS, Curley SA, Gallick GE (1993) J Clin Invest 91:53–60
Luttrell DK, Lee A, Lansing TJ, Crosby RM, Jung KD, Willard D, Luther M, Rodriguez M, Berman J, Gilmer TM (1994) Proc Natl Acad Sci U S A 91:83–87
Hitosugi T, Sato M, Sasaki K, Umezawa Y (2007) Cancer Res 67:8139–8148
Ji L, Roth JA (2008) J ThoracOncol 3:327–330
Uno F, Sasaki J, Nishizaki M, Carboni G, Xu K, Atkinson EN, Kondo M, Minna JD, Roth JA, Ji L (2004) Cancer Res 64:2969–2976
Resh MD (2006) Methods 40:191–197
Tate EW (2008) J Chem Biol 1:17–26
Drisdel RC, Green WN (2004) Biotechniques 36:276–285
Roth AF, Wan J, Bailey AO, Sun B, Kuchar JA, Green WN, Phinney BS, Yates Iii JR, Davis NG (2006) Cell 125:1003–1013
Kang R, Wan J, Arstikaitis P, Takahashi H, Huang K, Bailey AO, Thompson JX, Roth AF, Drisdel RC, Mastro R, Green WN, Yates Iii JR, Davis NG, El-Husseini A (2008) Nature 456:904–909
Heal WP, Wickramasinghe SR, Tate EW (2008) Curr Drug Discov Technol 5:200–212
Gamblin DP, van Kasteren SI, Chalker JM, Davis BG (2008) Febs J 275:1949–1959
Hang HC, Geutjes EJ, Grotenbreg G, Pollington AM, Bijlmakers MJ, Ploegh HL (2007) J Am Chem Soc 129:2744–2745
Saxon E, Bertozzi CR (2000) Science 287:2007–2010
Maja Köhn RB (2004) Angew Chem Int Ed 43:3106–3116
Kostiuk MA, Corvi MM, Keller BO, Plummer G, Prescher JA, Hangauer MJ, Bertozzi CR, Rajaiah G, Falck JR, Berthiaume LG (2007) FASEB J 22:721–732
Heal WP, Wickramasinghe SR, Bowyer PW, Holder AA, Smith DF, Leatherbarrow RJ, Tate EW (2008) Chem Commun 4:480–482
Heal WP, Wickramasinghe SR, Leatherbarrow RJ, Tate EW (2008) Org Biomol Chem 6:2308–2315
Agard NJ, Baskin JM, Prescher JA, Lo A, Bertozzi CR (2006) ACS Chem Biol 1:644–648
Charron G, Zhang MZM, Yount JS, Wilson J, Raghavan AS, Shamir E, Hang HC (2009) J Am Chem Soc 131:4967–4975
Martin BR, Cravatt BF (2009) Nature Methods 6:135–138
Hannoush RN, Arenas-Ramirez N (2009) ACS Chem Biol 4:581–587
Acknowledgments
MHW thanks the Chemical Biology Centre, Imperial College London, for the award of a studentship. WPH is supported by a Research Project Grant from Cancer Research UK to EWT and DJM (grant C29637/A9913). EWT thanks the Biotechnology and Biological Sciences Research Council (BBSRC), UK, for the award of a David Phillips Research Fellowship (grant BB/D02014X/1).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wright, M.H., Heal, W.P., Mann, D.J. et al. Protein myristoylation in health and disease. J Chem Biol 3, 19–35 (2010). https://doi.org/10.1007/s12154-009-0032-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12154-009-0032-8