Chemistry and biology of mammalian metallothioneins

  • Milan VašákEmail author
  • Gabriele Meloni


Metallothioneins (MTs) are a class of ubiquitously occurring low molecular mass, cysteine- and metal-rich proteins containing sulfur-based metal clusters formed with Zn(II), Cd(II), and Cu(I) ions. In mammals, four distinct MT isoforms designated MT-1 through MT-4 exist. The first discovered MT-1/MT-2 are widely expressed isoforms, whose biosynthesis is inducible by a wide range of stimuli, including metals, drugs, and inflammatory mediators. In contrast, MT-3 and MT-4 are noninducible proteins, with their expression primarily confined to the central nervous system and certain squamous epithelia, respectively. MT-1 through MT-3 have been reported to be secreted, suggesting that they may play different biological roles in the intracellular and extracellular space. Recent reports established that these isoforms play an important protective role in brain injury and metal-linked neurodegenerative diseases. In the postgenomic era, it is becoming increasingly clear that MTs fulfill multiple functions, including the involvement in zinc and copper homeostasis, protection against heavy metal toxicity, and oxidative damage. All mammalian MTs are monomeric proteins, containing two metal–thiolate clusters. In this review, after a brief summary of the historical milestones of the MT-1/MT-2 research, the recent advances in the structure, chemistry, and biological function of MT-3 and MT-4 are discussed.


Zinc Copper Mammalian metallothioneins Metal–thiolate clusters Neurodegenerative diseases 



Parts of the work described in this review have been funded over the years by the Swiss National Science Foundation (M.V.). G.M. is a Marie Curie International Outgoing Fellow (European Commission, grant no. 252961).


  1. 1.
    Margoshes M, Vallee BL (1957) J Am Chem Soc 79:4813–4814Google Scholar
  2. 2.
    Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M (1991) Neuron 7:337–347PubMedGoogle Scholar
  3. 3.
    Quaife CJ, Findley SD, Erickson JC, Froelick GJ, Kelly EJ, Zambrowicz BP, Palmiter RD (1994) Biochemistry 33:7250–7259PubMedGoogle Scholar
  4. 4.
    Miles AT, Hawksworth GM, Beattie JH, Rodilla V (2000) Crit Rev Biochem Mol Biol 35:35–70PubMedGoogle Scholar
  5. 5.
    Masters BA, Quaife CJ, Erickson JC, Kelly EJ, Froelick GJ, Zambrowicz BP, Brinster RL, Palmiter RD (1994) J Neurosci 14:5844–5857PubMedGoogle Scholar
  6. 6.
    Coyle P, Philcox JC, Carey LC, Rofe AM (2002) Cell Mol Life Sci 59:627–647PubMedGoogle Scholar
  7. 7.
    Duncan KER, Stillman MJ (2006) J Inorg Biochem 100:2101–2107Google Scholar
  8. 8.
    Stillman MJ (1995) Coord Chem Rev 144:461–511Google Scholar
  9. 9.
    Hidalgo J, Aschner M, Zatta P, Vašák M (2001) Brain Res Bull 55:133–145PubMedGoogle Scholar
  10. 10.
    West AK, Hidalgo J, Eddins D, Levin ED, Aschner M (2008) Neurotoxicology 29:489–503PubMedGoogle Scholar
  11. 11.
    Krezel A, Hao Q, Maret W (2007) Arch Biochem Biophys 463:188–200PubMedGoogle Scholar
  12. 12.
    Henkel G, Krebs B (2004) Chem Rev 104:801–824PubMedGoogle Scholar
  13. 13.
    Cherian MG, Jayasurya A, Bay BH (2003) Mutat Res 533:201–209PubMedGoogle Scholar
  14. 14.
    Theocharis SE, Margeli AP, Klijanienko JT, Kouraklis GP (2004) Histopathology 45:103–118PubMedGoogle Scholar
  15. 15.
    Vašák M, Hasler DW (2000) Curr Opin Chem Biol 4:177–183PubMedGoogle Scholar
  16. 16.
    Vašák M, Romero-Isart N (2005) In: King RB (ed) Encyclopedia of inorganic chemistry, 2nd edn. Wiley, New York, pp 3208–3221Google Scholar
  17. 17.
    Vallee BL (1979) Experientia Suppl 34:19–39PubMedGoogle Scholar
  18. 18.
    Maliuga DP (1941) Dokl Akad Nauk USSR 31(2):145Google Scholar
  19. 19.
    Kägi JHR, Vallee B (1960) J Biol Chem 235:3460–3465PubMedGoogle Scholar
  20. 20.
    Kojima Y, Berger C, Vallee BL, Kägi JHR (1976) Proc Natl Acad Sci USA 73:3413–3417PubMedGoogle Scholar
  21. 21.
    Gouy M, Guindon S, Gascuel O (2010) Mol Biol Evol 27:221–224PubMedGoogle Scholar
  22. 22.
    Piscator M (1964) Nordisk Hygienisk Tidskrift. XLV:76–82Google Scholar
  23. 23.
    Nordberg M, Kojima Y (1979) In: Kägi JHR, Nordberg M (eds) Metallothionein. Birkhäuser, Basel, pp 41–116Google Scholar
  24. 24.
    Michalska AE, Choo KHA (1993) Proc Natl Acad Sci USA 90:8088–8092PubMedGoogle Scholar
  25. 25.
    Masters BA, Kelly EJ, Quaife CJ, Brinster RL, Palmiter RD (1994) Proc Natl Acad Sci USA 91:584–588PubMedGoogle Scholar
  26. 26.
    Liu Y, Liu J, Iszard MB, Andrews GK, Palmiter RD, Klaassen CD (1995) Toxicol Appl Pharmacol 135:222–228PubMedGoogle Scholar
  27. 27.
    Durnam DM, Palmiter RD (1987) Experientia Suppl 52:457–463PubMedGoogle Scholar
  28. 28.
    Palmiter RD (1998) Proc Natl Acad Sci USA 95:8428–8430PubMedGoogle Scholar
  29. 29.
    Vallee BL (1987) Experientia Suppl 52:5–16PubMedGoogle Scholar
  30. 30.
    Searle PF, Davison BL, Stuart GW, Wilkie TM, Norstedt G, Palmiter RD (1984) Mol Cell Biol 4:1221–1230PubMedGoogle Scholar
  31. 31.
    Hamer DH (1986) Annu Rev Biochem 55:913–951PubMedGoogle Scholar
  32. 32.
    West AK, Stallings R, Hildebrand CE, Chiu R, Karin M, Richards RI (1990) Genomics 8:513–518PubMedGoogle Scholar
  33. 33.
    Palmiter RD, Findley SD, Whitmore TE, Durnam DM (1992) Proc Natl Acad Sci USA 89:6333–6337PubMedGoogle Scholar
  34. 34.
    Heuchel R, Radtke F, Georgiev O, Stark G, Aguet M, Schaffner W (1994) EMBO J 13:2870–2875PubMedGoogle Scholar
  35. 35.
    Chapman GA, Kay J, Kille P (1999) Biochim Biophys Acta 1445:321–329PubMedGoogle Scholar
  36. 36.
    Udom AO, Brady FO (1980) Biochem J 187:329–335PubMedGoogle Scholar
  37. 37.
    Zeng J, Heuchel R, Schaffner W, Kägi JH (1991) FEBS Lett 279:310–312PubMedGoogle Scholar
  38. 38.
    Zeng J, Vallee BL, Kägi JH (1991) Proc Natl Acad Sci USA 88:9984–9988PubMedGoogle Scholar
  39. 39.
    Thornalley PJ, Vašák M (1985) Biochim Biophys Acta 827:36–44PubMedGoogle Scholar
  40. 40.
    Sato M, Bremner I (1993) Free Radic Biol Med 14:325–337PubMedGoogle Scholar
  41. 41.
    Vašák M (1980) J Am Chem Soc 102:3953–3955Google Scholar
  42. 42.
    Otvos JD, Armitage IM (1980) Proc Natl Acad Sci USA 77:7094–7098PubMedGoogle Scholar
  43. 43.
    Vašák M, Kägi JH (1981) Proc Natl Acad Sci USA 78:6709–6713PubMedGoogle Scholar
  44. 44.
    Boulanger Y, Armitage IM, Miklossy KA, Winge DR (1982) J Biol Chem 257:13717–13719PubMedGoogle Scholar
  45. 45.
    Bertini I, Luchinat C, Messori L, Vašák M (1989) J Am Chem Soc 111:7296–7300Google Scholar
  46. 46.
    Stillman MJ, Zelazowski AJ (1988) J Biol Chem 263:6128–6133PubMedGoogle Scholar
  47. 47.
    Good M, Hollenstein R, Sadler PJ, Vašák M (1988) Biochemistry 27:7163–7166PubMedGoogle Scholar
  48. 48.
    Frey MH, Wagner G, Vašák M, Sorensen OW, Neuhaus D, Wörgötter E, Kägi JHR, Ernst RR, Wüthrich K (1985) J Am Chem Soc 107:6847–6851Google Scholar
  49. 49.
    Furey WF, Robbins AH, Clancy LL, Winge DR, Wang BC, Stout CD (1986) Science 231:704–710PubMedGoogle Scholar
  50. 50.
    Vašák M, Wörgötter E, Wagner G, Kägi JH, Wüthrich K (1987) J Mol Biol 196:711–719PubMedGoogle Scholar
  51. 51.
    Schultze P, Wörgötter E, Braun W, Wagner G, Vašák M, Kägi JH, Wüthrich K (1988) J Mol Biol 203:251–268PubMedGoogle Scholar
  52. 52.
    Arseniev A, Schultze P, Wörgötter E, Braun W, Wagner G, Vašák M, Kägi JHR, Wüthrich K (1988) J Mol Biol 201:637–657PubMedGoogle Scholar
  53. 53.
    Messerle BA, Schäffer A, Vašák M, Kägi JH, Wüthrich K (1990) J Mol Biol 214:765–779PubMedGoogle Scholar
  54. 54.
    Messerle BA, Schäffer A, Vašák M, Kägi JH, Wüthrich K (1992) J Mol Biol 225:433–443PubMedGoogle Scholar
  55. 55.
    Robbins AH, McRee DE, Williamson M, Collett SA, Xuong NH, Furey WF, Wang BC, Stout CD (1991) J Mol Biol 221:1269–1293PubMedGoogle Scholar
  56. 56.
    Braun W, Vašák M, Robbins AH, Stout CD, Wagner G, Kägi JH, Wüthrich K (1992) Proc Natl Acad Sci USA 89:10124–10128PubMedGoogle Scholar
  57. 57.
    Sewell AK, Jensen LT, Erickson JC, Palmiter RD, Winge DR (1995) Biochemistry 34:4740–4747PubMedGoogle Scholar
  58. 58.
    Palmiter RD (1995) Toxicol Appl Pharmacol 135:139–146PubMedGoogle Scholar
  59. 59.
    Irie Y, Keung WM (2001) Biochem Biophys Res Commun 282:416–420PubMedGoogle Scholar
  60. 60.
    Quaife CJ, Kelly EJ, Masters BA, Brinster RL, Palmiter RD (1998) Toxicol Appl Pharmacol 148:148–157PubMedGoogle Scholar
  61. 61.
    Penkowa M, Tio L, Giralt M, Quintana A, Molinero A, Atrian S, Vašák M, Hidalgo J (2006) J Neurosci Res 83:974–984PubMedGoogle Scholar
  62. 62.
    Hozumi I, Suzuki JS, Kanazawa H, Hara A, Saio M, Inuzuka T, Miyairi S, Naganuma A, Tohyama C (2008) Neurosci Lett 438:54–58PubMedGoogle Scholar
  63. 63.
    Yamada M, Hayashi S, Hozumi I, Inuzuka T, Tsuji S, Takahashi H (1996) Brain Res 735:257–264PubMedGoogle Scholar
  64. 64.
    Uchida Y, Gomi F, Masumizu T, Miura Y (2002) J Biol Chem 277:32353–32359PubMedGoogle Scholar
  65. 65.
    Lynes MA, Zaffuto K, Unfricht DW, Marusov G, Samson JS, Yin X (2006) Exp Biol Med (Maywood) 231:1548–1554Google Scholar
  66. 66.
    Chung RS, Penkowa M, Dittmann J, King CE, Bartlett C, Asmussen JW, Hidalgo J, Carrasco J, Leung YK, Walker AK, Fung SJ, Dunlop SA, Fitzgerald M, Beazley LD, Chuah MI, Vickers JC, West AK (2008) J Biol Chem 283:15349–15358PubMedGoogle Scholar
  67. 67.
    Klassen RB, Crenshaw K, Kozyraki R, Verroust PJ, Tio L, Atrian S, Allen PL, Hammond TG (2004) Am J Physiol Renal Physiol 287:F393–F403PubMedGoogle Scholar
  68. 68.
    Erickson JC, Hollopeter G, Thomas SA, Froelick GJ, Palmiter RD (1997) J Neurosci 17:1271–1281PubMedGoogle Scholar
  69. 69.
    Cole TB, Robbins CA, Wenzel HJ, Schwartzkroin PA, Palmiter RD (2000) Epilepsy Res 39:153–169PubMedGoogle Scholar
  70. 70.
    Aschner M, Cherian MG, Klaassen CD, Palmiter RD, Erickson JC, Bush AI (1997) Toxicol Appl Pharmacol 142:229–242PubMedGoogle Scholar
  71. 71.
    Knipp M, Meloni G, Roschitzki B, Vašák M (2005) Biochemistry 44:3159–3165PubMedGoogle Scholar
  72. 72.
    El Ghazi I, Martin BL, Armitage IM (2006) Exp Biol Med (Maywood) 231:1500–1506Google Scholar
  73. 73.
    Meloni G, Polanski T, Braun O, Vašák M (2009) Biochemistry 48:5700–5707PubMedGoogle Scholar
  74. 74.
    Assaf SY, Chung SH (1984) Nature 308:734–736PubMedGoogle Scholar
  75. 75.
    Palumaa P, Eriste E, Njunkova O, Pokras L, Jornvall H, Sillard R (2002) Biochemistry 41:6158–6163PubMedGoogle Scholar
  76. 76.
    Kang YJ (1999) Proc Soc Exp Biol Med 222:263–273PubMedGoogle Scholar
  77. 77.
    Liu J, Liu Y, Hartley D, Klaassen CD, Shehin-Johnson SE, Lucas A, Cohen SD (1999) J Pharmacol Exp Ther 289:580–586PubMedGoogle Scholar
  78. 78.
    Carrasco J, Penkowa M, Giralt M, Camats J, Molinero A, Campbell IL, Palmiter RD, Hidalgo J (2003) Neurobiol Dis 13:22–36PubMedGoogle Scholar
  79. 79.
    Chen Y, Irie Y, Keung WM, Maret W (2002) Biochemistry 41:8360–8367PubMedGoogle Scholar
  80. 80.
    Durand J, Meloni G, Talmard C, Vašák M, Faller P (2010) Metallomics 2:741–744PubMedGoogle Scholar
  81. 81.
    Lee SJ, Koh JY (2010) Mol Brain 3:30PubMedGoogle Scholar
  82. 82.
    Garrett SH, Sens MA, Shukla D, Nestor S, Somji S, Todd JH, Sens DA (1999) Prostate 41:196–202PubMedGoogle Scholar
  83. 83.
    Sens MA, Somji S, Garrett SH, Beall CL, Sens DA (2001) Am J Pathol 159:21–26PubMedGoogle Scholar
  84. 84.
    Tanji K, Irie Y, Uchida Y, Mori F, Satoh K, Mizushima Y, Wakabayashi K (2003) Brain Res 976:125–129PubMedGoogle Scholar
  85. 85.
    Dutta R, Sens DA, Somji S, Sens MA, Garrett SH (2002) Prostate 52:89–97PubMedGoogle Scholar
  86. 86.
    Karotki AV, Vašák M (2009) J Biol Inorg Chem 14:1129–1138PubMedGoogle Scholar
  87. 87.
    Bogumil R, Faller P, Binz PA, Vašák M, Charnock JM, Garner CD (1998) Eur J Biochem 255:172–177PubMedGoogle Scholar
  88. 88.
    Faller P, Vašák M (1997) Biochemistry 36:13341–13348PubMedGoogle Scholar
  89. 89.
    Hasler DW, Faller P, Vašák M (1998) Biochemistry 37:14966–14973PubMedGoogle Scholar
  90. 90.
    Faller P, Hasler DW, Zerbe O, Klauser S, Winge DR, Vašák M (1999) Biochemistry 38:10158–10167PubMedGoogle Scholar
  91. 91.
    Hagen KS, Stephan DW, Holm RH (1982) Inorg Chem 21:3928–3936Google Scholar
  92. 92.
    Öz G, Zangger K, Armitage IM (2001) Biochemistry 40:11433–11441PubMedGoogle Scholar
  93. 93.
    Wang H, Zhang Q, Cai B, Li H, Sze KH, Huang ZX, Wu HM, Sun H (2006) FEBS Lett 580:795–800PubMedGoogle Scholar
  94. 94.
    Hasler DW, Jensen LT, Zerbe O, Winge DR, Vašák M (2000) Biochemistry 39:14567–14575PubMedGoogle Scholar
  95. 95.
    Ni FY, Cai B, Ding ZC, Zheng F, Zhang MJ, Wu HM, Sun HZ, Huang ZX (2007) Proteins 68:255–266PubMedGoogle Scholar
  96. 96.
    Romero-Isart N, Oliva B, Vašák M (2010) J Mol Model 16:387–394PubMedGoogle Scholar
  97. 97.
    Romero-Isart N, Jensen LT, Zerbe O, Winge DR, Vašák M (2002) J Biol Chem 277:37023–37028PubMedGoogle Scholar
  98. 98.
    Ding ZC, Ni FY, Huang ZX (2010) FEBS J 277:2912–2920PubMedGoogle Scholar
  99. 99.
    Bruinink A, Faller P, Sidler C, Bogumil R, Vašák M (1998) Chem Biol Interact 115:167–174PubMedGoogle Scholar
  100. 100.
    Erickson JC, Sewell AK, Jensen LT, Winge DR, Palmiter RD (1994) Brain Res 649:297–304PubMedGoogle Scholar
  101. 101.
    Vašák M, Meloni G (2009) In: Sigel A, Sigel H, Sigel RKO (eds) Metallothioneins and related chelators. Royal Society of Chemistry, Cambridge, pp 319–351Google Scholar
  102. 102.
    Faller P (2010) FEBS J 277:2921–2930PubMedGoogle Scholar
  103. 103.
    Roschitzki B, Vašák M (2002) J Biol Inorg Chem 7:611–616PubMedGoogle Scholar
  104. 104.
    Jensen LT, Peltier JM, Winge DR (1998) J Biol Inorg Chem 3:627–631Google Scholar
  105. 105.
    Pountney DL, Schauwecker I, Zarn J, Vašák M (1994) Biochemistry 33:9699–9705PubMedGoogle Scholar
  106. 106.
    Roschitzki B, Vašák M (2003) Biochemistry 42:9822–9828PubMedGoogle Scholar
  107. 107.
    Gaggelli E, Kozlowski H, Valensin D, Valensin G (2006) Chem Rev 106:1995–2044PubMedGoogle Scholar
  108. 108.
    Barnham KJ, Masters CL, Bush AI (2004) Nat Rev Drug Discov 3:205–214PubMedGoogle Scholar
  109. 109.
    Sogawa CA, Asanuma M, Sogawa N, Miyazaki I, Nakanishi T, Furuta H, Ogawa N (2001) Acta Med Okayama 55:1–9PubMedGoogle Scholar
  110. 110.
    Kawashima T, Doh-ura K, Torisu M, Uchida Y, Furuta A, Iwaki T (2000) Dement Geriatr Cogn Disord 11:251–262PubMedGoogle Scholar
  111. 111.
    Hozumi I, Asanuma M, Yamada M, Uchida Y (2004) J Health Sci 50:323–331Google Scholar
  112. 112.
    Barnham KJ, Cappai R, Beyreuther K, Masters CL, Hill AF (2006) Trends Biochem Sci 31:465–472PubMedGoogle Scholar
  113. 113.
    Halliwell B, Gutteridge JM (1984) Biochem J 219:1–14PubMedGoogle Scholar
  114. 114.
    Meloni G, Faller P, Vašák M (2007) J Biol Chem 282:16068–16078PubMedGoogle Scholar
  115. 115.
    Meloni G, Sonois V, Delaine T, Guilloreau L, Gillet A, Teissie J, Faller P, Vašák M (2008) Nat Chem Biol 4:366–372PubMedGoogle Scholar
  116. 116.
    Chung RS, Howells C, Eaton ED, Shabala L, Zovo K, Palumaa P, Sillard R, Woodhouse A, Bennett WR, Ray S, Vickers JC, West AK (2010) PLoS One 5:e12030PubMedGoogle Scholar
  117. 117.
    Adlard PA, West AK, Vickers JC (1998) Neurobiol Dis 5:349–356PubMedGoogle Scholar
  118. 118.
    Richarz AN, Bratter P (2002) Anal Bioanal Chem 372:412–417PubMedGoogle Scholar
  119. 119.
    Zambenedetti P, Giordano R, Zatta P (1998) J Chem Neuroanat 15:21–26PubMedGoogle Scholar
  120. 120.
    Carrasco J, Adlard P, Cotman C, Quintana A, Penkowa M, Xu F, Van Nostrand WE, Hidalgo J (2006) Neuroscience 143:911–922PubMedGoogle Scholar
  121. 121.
    Adlard PA, Bush AI (2006) J Alzheimers Dis 10:145–163PubMedGoogle Scholar
  122. 122.
    Dawson TM, Dawson VL (2003) Science 302:819–822PubMedGoogle Scholar
  123. 123.
    Paik SR, Shin HJ, Lee JH (2000) Arch Biochem Biophys 378:269–277PubMedGoogle Scholar
  124. 124.
    Binolfi A, Lamberto GR, Duran R, Quintanar L, Bertoncini CW, Souza JM, Cervenansky C, Zweckstetter M, Griesinger C, Fernandez CO (2008) J Am Chem Soc 130:11801–11812PubMedGoogle Scholar
  125. 125.
    Drew SC, Leong SL, Pham CL, Tew DJ, Masters CL, Miles LA, Cappai R, Barnham KJ (2008) J Am Chem Soc 130:7766–7773PubMedGoogle Scholar
  126. 126.
    Aguzzi A, Heikenwalder M (2006) Nat Rev Microbiol 4:765–775PubMedGoogle Scholar
  127. 127.
    Prusiner SB (1991) Science 252:1515–1522PubMedGoogle Scholar
  128. 128.
    Meloni G, Vašák M (2011) Free Radic Biol Med 50:1471–1479PubMedGoogle Scholar
  129. 129.
    Liang L, Fu K, Lee DK, Sobieski RJ, Dalton T, Andrews GK (1996) Mol Reprod Dev 43:25–37PubMedGoogle Scholar
  130. 130.
    Schlake T, Boehm T (2001) Mech Dev 109:419–422PubMedGoogle Scholar
  131. 131.
    Meloni G, Zovo K, Kazantseva J, Palumaa P, Vašák M (2006) J Biol Chem 281:14588–14595PubMedGoogle Scholar
  132. 132.
    Cai B, Zheng Q, Huang ZX (2005) Protein J 24:327–336PubMedGoogle Scholar
  133. 133.
    Tio L, Villarreal L, Atrian S, Capdevila M (2004) J Biol Chem 279:24403–24413PubMedGoogle Scholar
  134. 134.
    Capdevila M, Domenech J, Pagani A, Tio L, Villarreal L, Atrian S (2005) Angew Chem Int Ed 44:4618–4622Google Scholar
  135. 135.
    Tio L, Villarreal L, Atrian S, Capdevila M (2006) Exp Biol Med (Maywood) 231:1522–1527Google Scholar
  136. 136.
    Prange A, Profrock D (2005) Anal Bioanal Chem 383:372–389PubMedGoogle Scholar
  137. 137.
    Mounicou S, Ouerdane L, L’Azou B, Passagne I, Ohayon-Courtes C, Szpunar J, Lobinski R (2010) Anal Chem 82:6947–6957PubMedGoogle Scholar

Copyright information

© SBIC 2011

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of ZurichZurichSwitzerland
  2. 2.Department of Inorganic ChemistryUniversity of ZurichZurichSwitzerland
  3. 3.Division of Chemistry and Chemical Engineering and Howard Hughes Medical InstituteCalifornia Institute of TechnologyPasadenaUSA

Personalised recommendations