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MetallothioneinsMetallothioneins
The real stateThe real state--ofof--thethe--artartThe real stateThe real state--ofof--thethe--artart
Òscar PalaciosÒscar PalaciosDept QuímicaDept QuímicaDept. QuímicaDept. QuímicaUniversitat Autònoma de BarcelonaUniversitat Autònoma de Barcelona
MetallothioneinsMetallothioneins ((MTsMTs))MetallothioneinsMetallothioneins ((MTsMTs)) Ubiquitous proteins: animals plants Ubiquitous proteins: animals, plants,
prokaryotes Small metalloproteins (40-100 aa)Small metalloproteins (40 100 aa) High sequence heterogeneity General absence of aromatic amino acids Cysteine-rich (~ 30 %) High metal-chelating capacity (thiol groups)g g p y ( g p ) No 3D structure of the apo form
structuration related with the formation of metal clusters
Biological role: metal homeostasis and detoxification, radical scavenging, …
HistoricalHistorical overviewoverviewHistoricalHistorical overviewoverview Scifinder: ~140000 results ISI Web of Knowledge: ~13000 results (papers, books and
reviews) PubMed: ~10000 results
600
700
MTI
MTII
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f pub
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MTIII MTIV
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200MTIII
0
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Years
HistoricalHistorical overviewoverviewHistoricalHistorical overviewoverview Fields of interest on MTs: a clear Fields of interest on MTs: a clear
change in tendency
BIOL TRACEENVIRON.
2007‐2011COMP. BIOCHEM. PHYSIOL. C‐ PROC NAT
1990‐1995
BIOL. TRACE ELEMENT
RES.BIOMETALS
ENVIRON
CHEMOSPHERE
POLLUTIONJOURNAL OF BIOLOGICAL CHEMISTRY
PHARMACOL. TOXICOL.
ENDOCRINOL.TOXICOL. LETTERS
PROC. NAT. ACAD.
SCIENCES USA
ECOTOXICOL. ENVIRON. SAFETY
COMP. BIOCHEM.
ARCH. ENVIRON. CONTAM. TOXICOL.
ENVIRON. TOXICOL. CHEM.METH. ENZYM.
BIOCHEM. J.
TOXICOLOGY
PHYSIOL. C‐TOXICOL.
PHARMACOL.
AQUATIC TOXICOL.
TOXICOL. APPL. PHARMACOL.
BIOL. TRACE ELEMENT RES.
MOL. CEL. BIOL.
TOXICOL. APPL. PHARMACOL.
Accepted features (end of the Accepted features (end of the
Classification of MTs in three classes90’s)90’s) Classification of MTs in three classes Coordination only by Cys residues Native complexes = metal-thiolates (in vivo Native complexes = metal-thiolates (in vivo
= in vitro) Ag(I) as model of Cu(I) and Cd(II) as model Ag(I) as model of Cu(I) and Cd(II) as model
of Zn(II) in Cu-MT and Zn-MT Very fast metal-substitution reactionsVery fast metal substitution reactions The amounts of metal added accounts for the
metal-MT stoichiometry, until saturation of the y,protein
Higher organisms: bidominial Zn-MTsg g Lower organisms: monodominial Cu-MTs
Zn7-MT1Cd7-MT1(mamals)
Cu8-Cup1 (yeast)
Inflexion point in the MTs fieldInflexion point in the MTs fieldInflexion point in the MTs fieldInflexion point in the MTs field
R bi t th iRecombinant synthesisof MTs
MTs of manyMTs of many organisms High purity
and high t
Mutant forms
amounts
First steps in the MTs fieldFirst steps in the MTs fieldFirst steps in the MTs fieldFirst steps in the MTs field
Pilar & Roser Gonzalez-Duarte(UAB) (UB)(UAB) (UB)
Mercè Capdevila & Sílvia Atrian(UAB) (UB)
E. coli culturesGenetic engineering
Metal-MT complexes
Chemical characterization
Metal-binding features
Sequence / function relationship
Classification, Evolutionary differentiation, Function
Experimental approachExperimental approachExperimental approachExperimental approach
In vivo Recombinant MT synthesis (wild type, domains or mutants)
Cd(II) Cu(II) Zn(II) Supplemented media
Acidification & Cd(II) Cu(I)
CdII‐MT CuI‐MTZnII‐MT
reneutralization( )
titration( )
titration
CdII MT CuI MT
In vitroCdII‐MT CuI‐MT
Experimental strategiesExperimental strategiesExperimental strategiesExperimental strategies
Atomic Emission
CD & UV-Vis- Metal-MT folding degree- Chromophores
Mass Spectrometry (ESI-MS)- Stoichiometry
Spectrometry (ICP-AES)- Protein concentration- Global metal-MT Stoichiometry
I t l Tit ti
- Stoichiometry- Molecular distribution of the existing metal-MT complexes
Isotermal Titration Calorimetry (ITC)- Thermodinamics
00
6
-4
-2
0
Data: A120509CUP1P_NDHModel: OneSitesChi^2/DoF = 3.386E4N 3.96 ±0.0698K 3.15E5 ±3.93E4H -7731 ±200 5/m
ole
of in
ject
ant
6
-4
-2
0
Data: A120509CUP1P_NDHModel: OneSitesChi^2/DoF = 3.386E4N 3.96 ±0.0698K 3.15E5 ±3.93E4H -7731 ±200 5/m
ole
of in
ject
ant
0 2 4 6 8 10 12-8
-6 H 7731 ±200.5S 0.855
Molar Ratio
kcal
/
0 2 4 6 8 10 12-8
-6 H 7731 ±200.5S 0.855
Molar Ratio
kcal
/
ProchordateProchordate
MT1 to MT4Villarreal et al., FEBS J., (2006), 273, 523
&
Artells et al., Metallomics, (2013)Tio et al., JBC, (2004), 279, 24403Bofill et al., JBIC, (2001), 6, 405Cols et al., Prot Engng., (1999), 12, 265
ProchordateProchordate
Valls et al., JBC, (2001), 276, 32835
Pagani et al., JIB, (2012), 117, 306
......
Guirola et al., PLos ONE, (2012), 7, e43299
&Domenech et al., JBIC, (2007), 12, 867Domenech et al., Biochimie, (2006), 88, 583
Tomás et al., FEBS OpenBio (2013)
Pérez-Rafael, ZAAC, (2013) Pérez-Rafael, JIB, (2012), 108 Palacios et al BMC (2011) 9:4
CeMT1 & CeMT2
Ding et al., Cell Host & Microbe (2013)C.neoformans
Orihuela et al., JBIC, (2008), 13, 801
Palacios et al., BMC, (2011), 9:4Höckner et al., Biometals, (2011), 24, 1079Pérez-Rafael, Metallomics, (2012), 4, 342
Egli et al., Genes to Cells, (2006), 11, 647Domenech et al., FEBS Lett., (2003), 533, 72Valls et al., FEBS Lett., (2000), 467, 189
CUP1 Crs5
Domenech et al., BBA, (2008), 1784, 693Bofill et al., FEBS J, (2009), 276, 7040
Pagani et al., Mol. Microbiol., (2007), 63, 256
Orihuela et al., Chem. Eur. J., (2010), 16, 12363
Diverse MTs discovered and Diverse MTs discovered and studiedstudied
H MT1Human MT1MDPNCSCAAGVSCTCAGSCKCKECKCTSCKKSCCSCCPVGCSKCAQGCVCKGASEKCSCCD
C.elegans MT1MACKCDCKNKQCKCGDKCECSGDKCCEKYCCEEASEKKCCPAGCKGDCKCANCHCAEQKQCGDKTHQHQGTAAAH
MPCPCGSGCKCASQATKGSCNCGSDCKCGGDKKSACGCSE
D.melanogaster MTN
QsMT, plant MTMSCCGGNCGCGTGCKCGSGCGGCKMFPDISSEKTTTETLIVGVAPQKTHFEGSEMGVGAENGCKCGSNCTCDPCNCK
TpyMT1, Tetrahymena MT
MGVGAENGCKCGSNCTCDPCNCK
MDKVNNNCCCGENAKPCCTDPNSGCCCVSETNNCCKSDKKECCTGTGEGCKWTGCKCCQPAKSGCCCGDKAKACCTDPNSGCCCSSKTNKCCDSTNKTECKTCECCK
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes Cooperative processes Cooperative processes
Zn7-MT1 + 2 Cd(II)
St i hi t t f t l dd d Stoichiometry vs. amount of metal added
Ag(I) equivalents added
Ag2Zn3-MT1Ag1Zn3-MT1
XXXXZn4-MT111109876543210
X major species minor species
XXAg6Zn1-MT1Ag4Zn2-MT1
XXXAg3Zn2-MT1Ag2Zn3 MT1
XAg11-MT1XXXXAg9-MT1
O. Palacios et al., JBIC, (2003) 8: 831-842
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes Speed of metal substitution reactions Speed of metal substitution reactions
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes The role of Zn(II) as a structural ion The role of Zn(II) as a structural ion
CeMT1
MeMT-10-IV
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes Ag(I) as a model for Cu(I) in Cu-MT? Ag(I) as a model for Cu(I) in Cu-MT?
In mammalian MT1 only in the presence of Zn(II)(O. Palacios et al., JBIC (2003) 8: 831-842)Ag7-Cup1 different of Cu7- and Cu8-Cup1(C.W. Peterson et al., FEBS Lett (1996) 379:58-93)
Cd(II) d l f Z (II) Z MT? Cd(II) as a model for Zn(II) en Zn-MT?
S. cerevisiae Cup1Cd Cd S Cd SZn4 > Zn3, Zn5Cd5 >> Cd6S1 > Cd7S1
(Orihuela et al., Chem-Eur J (2010) 16:12363-12372)
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes M-MT species ¿in vivo = in vitro? M-MT species ¿in vivo = in vitro?
MeMTMeMT--1010--IVIV
The binding role of His residuesWheatWheatZnZn44--EEcc--11
CianobacteriaCianobacteriaZnZn44--SmtA SmtA
C. A. Blindauer, Proc Natl Acad Sci USA (2001) 98:9593-9598 E.A. Peroza, J Mol Biol (2009) 387:207-218
CyanobacteriaCyanobacteriaCyanobacteriaCyanobacteriaZnZn44--SmtA SmtA
WheatWheatZnZn EE 11ZnZn44--EEcc--11
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes A sulfide surprise: S2- ions involved in metal
M. Capdevila et al., Angew. Chem. Int. Ed., (2005), 44 4618
A sulfide surprise: S ions involved in metal binding44, 4618
Cd-SCys Cd-S2-
TEM
Crystallites
D.R. Winge et al., Metallothioneins, VCH, 1992
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes Evidence of the presence of S2- in native Evidence of the presence of S in native
complexes1st step of purification
Anionic Exchange Chromatography
1 step of purification
Cadmium-resistant S. cerevisiae strain 301N supplemented with 500 μM CdSO4 Size Exclusion Chromatography (Sephadex G-75)Size Exclusion Chromatography (Sephadex G 75)
ChromatogramCadmium
Purification of the cadmium rich fractions by two different procedures
FPLC size l i
Cd
(ppm
) exclusion
time (min)
Sulfide contribution at 280 nm
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes Participation of Cl- ions in metal binding Participation of Cl ions in metal binding Importance of the degree of oxigenation in the
E. coli cultures for the formation of Cu-MTE. coli cultures for the formation of Cu MT species
Importance of the purity of Zn-MT samples in p p y pmetal-replacement reactions
Fine tuning the classification of Fine tuning the classification of MTsMTs
• 1st Kägi’s classification: Mammalian-homology3 classes:
Class I: Homology to mammalian MT1Class II: Non-homology to mammalian MT1 (neither among them! )
1 Kägi s classification: Mammalian homology criteria
gy ( g )Class III: Phytochelatins (non gene-encoded peptides)
• 2nd Kägi’s classification: Taxonomic criteriaAn MT family for each taxon
• Zn/Cd-thioneins vs. Cu-thioneins Metal-MT complex features Protein sequence similarity analysis Gene inducibility criteria
Zinc-Thionein vs. copper-Thionein character of MTsValls et al JBC (2001) 276 32835
zinc (or cadmium) copper
Valls et al., JBC, (2001), 276, 32835
- heteronuclear Zn/Cd + Cu complexes- low folding and high oxidation
-fully-metalated metal complexes- high folding degree low oxidation low folding and high oxidation
degree- variable Zn/Cd, Cu content
high folding degree, low oxidation- one prevalent complex (with the expectable stoichiometry) and other minor forms
Zn/Cd-Th
- mixture of Zn (or Cd) species (different stoichiometries)stoichiometries)- variable folding and oxidation degree- two or more equally-prevalent
- fully-metalated copper complexes- high folding degree, low oxidation- one prevalent complex (with the expectable stoichiometry) and otherCu-Th stoichiometries
- requirement of additional ligands (for Cd2+), chloride, sulfide
expectable stoichiometry) and other minor forms
Cu-Th
New classification proposalNew classification proposalNew classification proposalNew classification proposalMouseMouse Chicken MT1Chicken MT1
Cu Zn ckMT1Cu-Zn MT1
Zn-thionein
Cu-Zn ckMT1Zn-thionein
But better for copper-Cu-Cu MT4
Cu-thionein
Tio et al., JBC, (2004), 279, 24403
ppcoordination than mMT1 !!!
Tio et al., JBC, (2004), 279, 24403
Lobster MTHLobster MTHVillarreal et al., FEBS J., (2006), 273, 5
MtnA (MTN)MtnB (MTO)
Fruit FlyFruit Fly
Cu-thioneins
(MTO)MtnCMtnD
Zn-Zn Zn-thionein Cu thioneins
Egli et al., Genes to Cells, (2006), 11, 6
Zn Zn Zn thionein
Valls et al., JBC, (2001), 276, 32835
Fine tuning of the classification of Fine tuning of the classification of MTMT
Bofill et al., Metallomics (2009), 1, 229Capdevila et al., (2010) Bioinorg Chem Appl 1-6 (doi:
Genuine Zn-thioneinsCeMT1 C. elegans p , ( ) g pp (
10.1155/2010/541829)Ce C e ega s
MeMT M. edulis
MT1 M. musculus
HpCdMT H pomatia 1 Presence/absence of ZnII in theHpCdMT H. pomatia
TpyMT1 T. pyriformis
SpMTA S. purpuratus
CkMT G ll
1. Presence/absence of ZnII in the biosynthesized Cu-MT species
2 Number of CuI equivalentsCkMT G. gallus
MTH H. americanus
CeMT2 C. elegans
2. Number of CuI equivalents (Cys/Cu ratio) required to in vitro reproduce the biosynthesized Cu-MT species
Crs5 S. cerevisiae
MT4 M. musculus
QsMT Q. suber
Cu MT species
3. Presence/absence of S2- and/or ZnII in the biosynthesized Cd-MT species
HpCuMT H. pomatia
MtnA D. melanogaster
MtnB D. melanogaster
y p
4. Reluctance to in vitro Zn/Cdsubstitution (lack of isostructurality
Cup1 S. cerevisiae
Genuine Cu-thioneins
between the Zn-MT and Cd-MT forms)
New insights into the features of New insights into the features of the metalthe metal--MT complexesMT complexes Effect of the non-binding amino acids
Mammalian Mammalian isoformsisoforms::
Effect of the non-binding amino acids
MT 4 MDPGECTCMSGGICICGDNCKCTTCSCKTCRKSCCPCCPPGCAKCARGCICKGGSDKCSCCP MT 1 MDP NCSCSTGGSCTCTSSCACKNCKCTSCKKSCCSCCPVGCSKCAQGCVCKGAADKCTCCA domain domain
Zn7-MT1Cu10-MT4
domain domain
HpCuMT MGRGKNCGGACNSNPCSCGNDCKCGAGCNCDRCSSCHCSNDDCKCGSQCTGSGSCKCGSACGCK
Snail Snail isoformsisoforms::HpCuMT MGRGKNCGGACNSNPCSCGNDCKCGAGCNCDRCSSCHCSNDDCKCGSQCTGSGSCKCGSACGCKHpCdMT MGKGKGEKCTSACRSEPCQCGSKCQCGEGCTCAACKTCNCTSDGCKCGKECTGPDSCKCGSSCSCK
Native: Cu12-HpCuMT & Cd6-HpCdMT (Palacios et al., (2011) BMC Biol 9:1-20 ) (Dallinger et al., Nature 1997)
CaCdMT MSGKGKGEKCTAACRNEPCQCGSKCQCGEGCTCAACKTCNCTSDGCKCGKECTGPDSCKCGSSCGCK CaCdCuMT MSGKG--SACAGSCNSNPCSCGDDCKCGAGCSCAQCYSCQCNNDTCKCGSQCSTSGSCKCGS-CGCK CaCuMT MSGRG QNCGGACNSNPCNCGNDCNCGTGCNCDQCSARHCSNDDCKCGSQCTRSGSCKCGNACGCKCaCuMT MSGRG--QNCGGACNSNPCNCGNDCNCGTGCNCDQCSARHCSNDDCKCGSQCTRSGSCKCGNACGCK
MammalianMammalian MetallothioneinsMetallothioneins((mMTsmMTs))MT1 MDPN-CSCSTGGSCTCTSSCACKNCKCTSCKKSCCSCCPVGCSKCAQGCVCKGA------ADKCTCCA 61
MT2 MDPN-CSCASDGSCSCAGACKCKQCKCTSCKKSCCSCCPVGCAKCSQGCICKEA------SDKCSCCA 61 MT4 MDPGECTCMSGGICICGDNCKCTTCSCKTCRKSCCPCCPPGCAKCARGCICKGG------SDKCSCCP 62
((mMTsmMTs))
MT3 MDPETCPCPTGGSCTCSDKCKCKGCKCTNCKKSCCSCCPAGCEKCAKDCVCKGEEGAKAEAEKCSCCQ 68
domain domain
Cu ZnMT4MT4MT3MT3 MT2MT2MT1MT1
MammalianMammalian MetallothioneinsMetallothioneins(( MTMT ))
Zn Cd Cu (≈ O2) Cu ( O2)
MT2 2
3
4
4x10Intens. 0 Cd(II)
Zn7
0 0
0.5
1.0
1.5
2.0
2.5
5x10Intens.
Cd7A
Cd7S2
500
1000
1500
2000
Intens. 15 Cd(II)
Zn1Cd7
Cd7
Zn1Cd6
0.00
0.25
0.50
0.75
1.00
1.25
5x10 Intens.
6600 6700 6800 6900 7000 7100 m/z
M10
M11
M7M9
M8
M12
M13
0
1
2
35x10
Intens.
6200 6400 6600 6800 7000 m/z
Cu10
Cu8
Cu4
Cu6
apo-MT
M7- to M13- composed of:
((mMTsmMTs))MT2
(Metallomics, 2013) 0
1
2
Zn7-MT2
0.06800 6900 7000 7100 7200 m/z 0
1660 1680 1700 1720 1740 1760 1780 m/z Cd7-MT2 Zn7-MT2
+ 15 Cd(II) eq (reluctance)
M7- to M13- composed of:ZnnCu10- ZnnCu6- ZnnCu8-
ZnnCu4-MT2
----------
Zn7 Cu11
MT1 (JBIC 2001)
(Talanta 2002)
Cd7-MT1 Zn7-MT1 + 9 Cd(II) eq ( l t )
Z C MT1Zn7-MT1 (reluctance) Zn3Cu7-MT1
Major Cu11-MT1
MT4 (JBC, 2004)
(Exp Biol MedM8- & M10- with major
Zn3Cu7-MT4
Zn7
(Exp. Biol. Med., 2006)
Zn7-MT4
Zn,Cd-MT4 + Cd-S2--MT4
Zn3Cu7 MT4
Major Cu10-MT4
3
5x10Intens.
Zn7 Zn-MT3
0.8
1.0
4x10Intens.
Cd7
0.6
0.8
1.0
5x10Intens.
M10
M11
pH 7.0A
3
4
5
5x10Intens.
Cu6
Cu10pH 2.4B
6
4x10Intens.
Cu10C
MT3 (submitted)
0
1
2
7400 7500 7600 7700 7800 7900 8000 8100 m/z
Zn5
Zn6
Zn7- > Zn6- > Zn5-MT3
0.0
0.2
0.4
0.6
7850 7900 7950 8000 8050 8100 m/z
Cd7S2
Cd8
Cd7- > Cd7S2- > Cd6-MT3
0.0
0.2
0.4
7500 7600 7700 7800 7900 8000 m/z
M11
M12
M9
0
1
2
7300 7400 7500 7600 7700 7800 m/z
Cu4
Cu8 Cu11
Major M10- composed of: Zn4Cu6-
Cu10-MT3 0
2
4
7650 7700 7750 7800 7850 7900 7950 8000 m/z
Cu11
Cu12
Cu13
Major Cu10-MT3
Metal specificity comes from the MT primary structure but neither Metal specificity comes from the MT primary structure but neither from its Cys content or position nor the metal ion availabilityfrom its Cys content or position nor the metal ion availability
Reactivity of ZnReactivity of Zn--mMTmMT complexes with complexes with PbPb2+2+
MT2MT2
MT1MT1
MT3MT3
MT3MT3 Cup1Cup1pp
ZnZn‐‐mMT + 10 PbmMT + 10 Pb2+2+Reactivity of ZnReactivity of Zn--mMTmMT complexes with complexes with PbPb2+2+
MT1 MT2 MT3 MT4
ZnZn‐‐mMT + 10 PbmMT + 10 PbPbPb
A562nmOrihuela et al., Chem. Commun, (2011), 47, 12155Iron release from Iron release from ferritinferritin by Znby Zn--MT complexesMT complexes
Zn-MT1 : 55.6%
Zn-MT2 : 23.9%3 9%
Zn-MT3 : 59.5%time(h)( )
(a) (b)
Zn7 Zn7
MT2MT2
MT1
Zn6
Zn5Zn4
Zn3Zn2
MT2
Zn7 Zn7
Zn7 Zn7
Z MT3MT3MT3
Zn6
Zn5Zn6
Zn5
Zn4Zn3
Zn2
MT3MT3
Metallothioneins: where are Metallothioneins: where are they?they?
Metallicthiolates Metalloproteins
Metallothioneins
Now we can say thatNow we can say thatNow we can say that …Now we can say that … Ag(I) andAg(I) and CdCd(II) cannot be always considered as models of(II) cannot be always considered as models ofAg(I) and Ag(I) and CdCd(II) cannot be always considered as models of (II) cannot be always considered as models of
Cu(I) and Zn(II) in MTs Cu(I) and Zn(II) in MTs In vivo In vivo formed species can be clearly different from those formed species can be clearly different from those
f df d i iti itformed formed in vitroin vitro The The stoichiometrystoichiometry of the species formed in a titration are not of the species formed in a titration are not
only dependent of the amount of metal presentonly dependent of the amount of metal presenty p py p p Zn(II) can play a structural role also in MTsZn(II) can play a structural role also in MTs The speed of metal replacement in MTs is dependent of The speed of metal replacement in MTs is dependent of
several factors (metal ion, protein, temperature, etc.)several factors (metal ion, protein, temperature, etc.) Evidence of the presence of SEvidence of the presence of S22-- ions as the third component ions as the third component
in metalin metal--MT complexes biosynthesized (recombinant andMT complexes biosynthesized (recombinant andin metalin metal MT complexes biosynthesized (recombinant and MT complexes biosynthesized (recombinant and native)native)
Metal specificity of each MT comes from their primary Metal specificity of each MT comes from their primary b t t f thb t t f th CC t t l ti iti it t l ti iti isequence but not from the sequence but not from the CysCys content or relative position in content or relative position in
the chainthe chain
Present and futurePresent and futurePresent and futurePresent and future Presence of S2- as additional ligands: Presence of S as additional ligands:◦ Structures of metal-S-MT species form◦ Role of S2-: redox process, homeostasis, etc.p , ,◦ Presence in other type of metallic complexes
Study of the interaction of MTs with other yproteins/species:◦ Interaction with radicals and role in the isomerization of
li idlipids◦ Reactivity with anticancer drugs (Pt, Ru, etc.)◦ Interaction with metalloproteins: hemocianin etc◦ Interaction with metalloproteins: hemocianin, etc.◦ Role in the detoxification of Pb(II) and Hg(II)Which is the role of MTs in each organism?
Which is their role in the different processesWhich is their role in the different processes where they can be found?
AcknowledgmentsAcknowledgmentsAcknowledgmentsAcknowledgmentsUNIVERSITAT DE BARCELONA
Ò. PalaciosR. OrihuelaM. TomasE. ArtellsS. Pérez-Rafael
C Pé ZúñiM. Capdevila
C. Pérez-Zúñiga
Projects: BIO2012-39682-C02-01 & 02
ColaboratorsColaboratorsColaboratorsColaborators
JHR Kägi W. Schaffner D. Winge V. PecoraroZürich,
SLC, Utah, Michigan
R. DallingerA TorreggianiJ M Domínguez
C. AndreoRosario,
Innsbruck,A. Torreggiani
Bologna,J. RuizMurcia
J.M. Domínguez-VeraGranada
MetallothioneinsMetallothioneins
The real stateThe real state--ofof--thethe--artartThe real stateThe real state--ofof--thethe--artart
Òscar PalaciosÒscar PalaciosDept QuímicaDept QuímicaDept. QuímicaDept. QuímicaUniversitat Autònoma de BarcelonaUniversitat Autònoma de Barcelona
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