Metalloproteins are essential for many cellular functions, but it has not been clear how they distinguish between the different metals to bind the correct ones. A report in BMC Biology finds that preferences of two metallothionein isoforms for two different cations are due to inherent properties of these usually less discriminating proteins. Here these observations are discussed in the context of the cellular mechanisms that regulate metal binding to proteins

A Changela

A Cvetkovic

Andrew W Foster

CE Outten

F da Silva

JD Helmann

KJ Waldron

Nigel J Robinson

S Tottey

T Dudev

Z Xiao

Ò Palacios

English

PubMed

Springer - Publisher Connector

Promiscuity and preferences of metallothioneins: the cell rules

Metals are essential to the structure and function of 
many proteins, from DNA-binding zinc fingers to 
respiratory proteins that require iron or copper. It has 
been estimated that nearly half of all enzymes are 
metalloproteins [1], although vast numbers of 
metalloproteins may remain uncharacterized [2]. A 
fundamental question about all such proteins is what 
determines which metals they bind. In some cases metals 
are delivered to the metalloproteins by specialized 
metallochaperones. But for most metalloproteins, a 
critical factor is thought to be the availability of the 
appropriate metal species in the buffered pools in the 
cell. These vital buffered metal pools need to be somehow 
measured.
Metallothionein proteins provide cysteine thiolate 
ligands for metals and constitute a part of the metal-
buffer in cells, both for storing biologically important 
metals and for sequestering toxic ones. These proteins 
usually show similar preferences to each other in the 
metals that they bind. In a recent paper in BMC Biology, 
Dallinger and colleagues (Palacios et al. [3]) report 
investigations on two metallothionein isoforms of snails 
that, despite having an identical number and arrangement 
of cysteine residues, seem to differ in their choice of 
copper or cadmium. The authors conclude that a high 
degree of metal selectivity is conferred by the inherent 
properties of the proteins.
Copper, cadmium and the biology of snail 
metallothioneins
The two metallothionein isoforms studied by Palacios et 
al. [3] are HpCuMT and HpCdMT from the Roman snail 
Helix pomatia. HpCuMT is constitutively expressed in 
snails in a specialized molluscan cell type, the rhogocyte, 
which is the site of synthesis of the copper protein 
hemocyanin [3]. As its name suggests, HpCuMT has 
always been recovered from the snail tissue as a 
homometallic copper protein. In contrast, HpCdMT is 
induced in many cell types in snails exposed to cadmium, 
and is recovered as a homometallic cadmium protein.
To find out whether the metals acquired by these 
proteins are due to the differential availability of the two 
metals at the site of synthesis of the metallothioneins or 
due to the inherent properties of the proteins, Palacios et 
al. expressed the two metallothioneins in Escherichia coli 
and yeast cells under conditions of varying metal 
exposure. In the presence of elevated copper and low 
oxygen, they recovered HpCuMT from E. coli as a 
homometallic copper protein whereas under the same 
conditions HpCdMT was recovered as a mixed species 
containing zinc (this protein is thought normally to 
buffer zinc but to bind cadmium after cadmium 
intoxication) as well as copper [3]. Conversely, when 
HpCdMT was expressed in E. coli enriched with either 
cadmium or zinc, homometallic, fully populated 
cadmium or zinc forms were recovered, although 
analogous expression of HpCuMT gave variable 
occupancy with cadmium or zinc [3]. The H. pomatia 
proteins also rescued sensitivity to cadmium or to copper 
in yeast mutants with metal sensitivities that matched the 
Abstract
Metalloproteins are essential for many cellular 
functions, but it has not been clear how they 
distinguish between the different metals to bind 
the correct ones. A report in BMC Biology finds that 
preferences of two metallothionein isoforms for two 
different cations are due to inherent properties of 
these usually less discriminating proteins. Here these 
observations are discussed in the context of the cellular 
mechanisms that regulate metal binding to proteins.
Promiscuity and preferences of metallothioneins: 
the cell rules
Andrew W Foster and Nigel J Robinson*
See research article: http://www.biomedcentral.com/1741-7007/9/4
CO M M E N TA RY  Open Access
*Correspondence: nigel.robinson@durham.ac.uk 
Biophysical Sciences Institute, Department of Chemistry, School of Biological and 
Biomedical Sciences, Durham University, DH1 3LE, UK
© 2011 Foster AW, Robinson NJ; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative 
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and 
reproduction in any medium, provided the original work is properly cited.
Foster AW, Robinson NJ BMC Biology 2011, 9:25
http://www.biomedcentral.com/1741-7007/9/25
metals selected by the respective metallothioneins. 
Retention of metal preferences in heterologous hosts 
argues that selectivity resides in the proteins. However, a 
heterologous environment still contains other proteins 
contributing to the buffering of metals, and these data do 
not necessarily mean, for example, that HpCdMT binds 
cadmium and/or zinc more tightly than copper. Rather, 
the data reflect the metal preferences of HpCdMT 
relative to other components of the mixed metal buffers 
of the organisms and cell types.
What determines the metal preferences of 
proteins?
Because proteins are flexible, they offer imperfect steric 
selection between metals. This is especially true of 
nascent proteins before folding. The affinities of proteins 
for metals are influenced by universal orders of 
preference, which for biologically essential divalent 
metals includes the Irving-Williams series (Figure 1a), 
which ranks the relative stability of complexes formed 
with each metal ion [4]. (Monovalent copper also forms 
tight associations with proteins, particularly when the 
ligands are cysteine thiolates, as in metallothioneins.) 
Several nonessential toxic metals, including mercury, 
cadmium and silver, also form tight complexes with 
thiolates, obeying an order of preference listed in Figure 
1b [3]. Under the strictures of such affinity series how do 
large numbers of proteins become populated with less 
competitive metals such as magnesium and manganese, 
avoiding displacement by more tightly binding metals 
such as copper? Part of the answer is that the buffered 
concentrations of metals are controlled in cells in such a 
way that the most competitive metals are bound and 
buffered to the lowest available concentrations. This is 
illustrated by the predominant manganese protein and 
the predominant copper protein in the periplasm of a 
cyanobacterium [5]. These proteins, MncA and CucA, 
respectively, have identical sets of metal ligands and 
similar cupin folds. Moreover, the manganese protein 
MncA has a 10,000 times greater preference for the 
wrong metal, copper, than for manganese. However, 
whereas the copper protein folds after membrane 
translocation, MncA folds in the cytosol before 
translocation. Therefore, the cytosol must be a protected 
environment where the ratio of buffered copper to 
buffered manganese is less than 1:10,000, at least at the 
site where MncA folds. Once the protein has correctly 
enfolded manganese, the metal becomes kinetically 
entrapped and safe from replacement by more 
competitive metals such as copper [5]. The folding 
location thus overrides the metal-binding preference of 
MncA to dictate metal occupancy. Precise control of the 
ratios of buffered metals available to proteins at folding is 
thus crucial to ensure binding of the correct inorganic 
Figure 1. Universal orders of metal preference and proposed 
buffered metal concentrations in cells. (a) The Irving-Williams 
series provides a preferred binding order for divalent metals. 
(b) An order of preference for thiolate-containing ligands of some 
nonessential, and some essential, metals. (c) How the occupancy of 
HpCdMT and HpCuMT might relate to the buffered concentrations 
of metals in a hypothetical cell. The total concentration of each metal 
in a cell (squares) is many orders of magnitude greater than the 
buffered concentration (circles), with the exception of bulk solutes 
such as sodium and potassium. The values have been adapted from 
a proposal of da Silva and Williams [4]. Proteins with affinities tighter 
than the buffered concentrations can acquire metals. HpCuMT (green 
triangles) is suggested to have an affinity for copper slightly tighter 
than the buffered concentration of copper found in many cell types, 
whereas HpCdMT (red triangles) is suggested to have a copper 
affinity too weak to compete effectively with the copper buffers of 
at least some cell types. In this scheme the situation is reversed for 
zinc. There is evidence that the relationship between the H. pomatia 
metallothioneins and buffers for non-cognate metals depart from 
this scheme in some cell types.
Tight
Mg < Ca < Mn < Fe < Co < Ni < Cu > Zn
(a)
Na K Mg Ca Mn Fe Co Ni Cu Zn
total
buffered
m
ill
i
m
ic
ro
na
no
pi
co
fe
m
to
m
illi
m
icro
nano
pico
fem
to
HpCdMT
HpCuMT
(c)
(b)
Weak Tight
Zn < Co < Pb < Cd < Cu / Ag < Hg
Weak
M
et
al
 c
on
ce
nt
ra
tio
n 
(m
ol
ar
)
M
etal affinity (m
olar)
Foster AW, Robinson NJ BMC Biology 2011, 9:25
http://www.biomedcentral.com/1741-7007/9/25
Page 2 of 3
elements. Computational studies similarly conclude that 
in biological systems, in the absence of metallo-
chaperones, the specificity of protein ligands for metals 
depends mainly on the local abundances of metals [6].
Binding affinity, competition and control of metal 
availability in cells
The availability of metals in cells is thought to be 
regulated by the actions of DNA-binding metal sensors 
that control the expression of genes encoding proteins of 
metal homeostasis, including metal-buffering proteins 
such as metallothioneins [1]. These sensors act to 
maintain the buffered concentrations of metals within 
limits determined, at least in part, by their own metal 
affinities [7]. Under such a regime the metal affinities of 
E. coli metal sensors will influence metal occupancy of 
snail metallothioneins when expressed in E. coli. The 
copper affinity of the E. coli copper sensor CueR, relative 
to the zinc affinities of the zinc sensors ZntR and Zur, 
suggests that copper is buffered to an even lower 
concentration than zinc [8,9] in E. coli. A protein is 
expected to gain access to a given metal only if the affinity 
of the protein for that metal is tighter than the buffered 
concentration. Thus, HpCuMT is predicted to have an 
affinity for copper tight enough to compete with other 
molecules that buffer copper in rhogocytes, and also in 
E.  coli and yeast. In contrast, HpCdMT is predicted to 
have an affinity for copper that is less able to compete 
with these other buffers (Figure 1c).
Measurement of the absolute metal affinities of 
proteins has been surprisingly challenging, with many 
erroneous values in the literature [10]. The copper, cad-
mium and zinc affinities of H. pomatia metallothioneins 
remain to be measured, but the scheme in Figure 1c 
suggests that HpCdMT and HpCuMT both have tighter 
affinities for copper than for cadmium or zinc, in 
accordance with the series in Figure 1a,b. Subtle 
differences between the two sequences must nonetheless 
give HpCuMT the tighter copper affinity of the two, as 
when both are expressed in the presence of excess copper 
in E. coli, only HpCuMT becomes fully populated with 
copper [3]. Notably, even after growth of E. coli in excess 
copper, recombinant HpCuMT was partly occupied with 
zinc unless the cells were also depleted of oxygen. 
Perhaps copper is buffered to a slightly lower 
concentration in aerobic E. coli than in rhogocytes, or 
perhaps the E. coli copper pool in aerobic conditions is 
swiftly depleted by overexpression of HpCuMT. There is 
no known demand for copper in the E. coli cytosol, 
although there is emerging evidence that periplasmic 
copper proteins are supplied with copper through export 
from the cytosol.
It is hypothesized that the metals that occupy proteins 
and are critical to their function could be regulated 
according to cell type by adjusting the buffered metal 
concentrations to different settings in different cell types. 
HpCuMT itself contributes to the copper buffer in 
rhogocytes, implying that copper is buffered more tightly 
in these cells than in other cells, perhaps to withhold 
copper more effectively from metalloproteins other than 
hemocyanin. Technologies are being developed to 
measure the elusive availabilities of metals to nascent 
proteins. The mechanisms that maintain these buffered 
concentrations underlie much of biological catalysis.
Acknowledgements
Work in the authors’ lab is supported by BBSRC research grants BB/H011110/2 
and BB/H006052/1.
Published: 28 April 2011
References
1. Waldron KJ, Rutherford JC, Ford D, Robinson NJ: Metalloproteins and metal 
sensing. Nature 2009, 460:823-830.
2. Cvetkovic A, Menon AL, Thorgersen MP, Scott JW, Poole FL 2nd, Jenney FE Jr, 
Lancaster WA, Praissman JL, Shanmukh S, Vaccaro BJ, Trauger SA, Kalisiak E, 
Apon JV, Siuzdak G, Yannone SM, Tainer JA, Adams MW: Microbial 
metalloproteomes are largely uncharacterized. Nature 2010, 466:779-782.
3. Palacios Ò, Pagani A, Pérez-Rafael S, Egg M, Höckner M, Brandstätter A, 
Capdevila M, Atrian S, Dallinger R: Shaping mechanisms of metal specificity 
in a family of metazoan metallothioneins: evolutionary differentiation of 
mollusc metallothioneins. BMC Biol 2011, 9:4.
4. da Silva F, Williams RJP: The Biological Chemistry of the Elements: The Inorganic 
Chemistry of Life. 2nd edition. New York: Oxford University Press; 2001.
5. Tottey S, Waldron KJ, Firbank SJ, Reale B, Bessant C, Sato K, Cheek TR, Gray J, 
Banfield MJ, Dennison C, Robinson NJ: Protein-folding location can regulate 
manganese-binding versus copper- or zinc-binding. Nature 2008, 
455:1138-1142.
6. Dudev T, Lim C: Metal binding affinity and selectivity in metalloproteins. 
Annu Rev Biophys 2008, 37:97-116.
7. Helmann JD, Soonsanga S, Gabriel S: Metalloregulators: arbiters of metal 
sufficiency. Microbiol Monogr 2007, 6:37-71.
8. Changela A, Chen K, Xue Y, Holschen J, Outten CE, O’Halloran TV, Mondragón 
A: Molecular basis of metal-ion selectivity and zeptomolar sensitivity by 
CueR. Science 2003, 301:1383-1387.
9. Outten CE, O’Halloran TV: Femtomolar sensitivity of metalloregulatory 
proteins controlling zinc homeostasis. Science 2001, 292:2488-2492.
10. Xiao Z, Wedd AG: The challenges of determining metal-protein affinities. 
Nat Prod Rep 2010, 27:768-789.
Foster AW, Robinson NJ BMC Biology 2011, 9:25
http://www.biomedcentral.com/1741-7007/9/25
doi:10.1186/1741-7007-9-25
Cite this article as: Foster AW, Robinson NJ: Promiscuity and preferences of 
metallothioneins: the cell rules. BMC Biology 2011, 9:25.
Page 3 of 3


Crossref

Metals are essential to the structure and function of many proteins, from DNA-binding zinc fingers to respiratory proteins that require iron or copper. It has been estimated that nearly half of all enzymes are metalloproteins [1], although vast numbers of metalloproteins may remain uncharacterized [2]. A fundamental question about all such proteins is what determines which metals they bind. In some cases metals are delivered to the metalloproteins by specialized metallochaperones. But for most metalloproteins, a critical factor is thought to be the availability of the appropriate metal species in the buffered pools in the cell. These vital buffered metal pools need to be somehow measured.Metallothionein proteins provide cysteine thiolate ligands for metals and constitute a part of the metal-buffer in cells, both for storing biologically important metals and for sequestering toxic ones. These proteins usually show similar preferences to each other in the metals that they bind. In a recent paper in BMC Biology, Dallinger and colleagues (Palacios et al. [3]) report investigations on two metallothionein isoforms of snails that, despite having an identical number and arrangement of cysteine residues, seem to differ in their choice of copper or cadmium. The authors conclude that a high degree of metal selectivity is conferred by the inherent properties of the proteins.Copper, cadmium and the biology of snail metallothioneinsThe two metallothionein isoforms studied by Palacios et al. [3] are HpCuMT and HpCdMT from the Roman snail Helix pomatia. HpCuMT is constitutively expressed in snails in a specialized molluscan cell type, the rhogocyte, which is the site of synthesis of the copper protein hemocyanin [3]. As its name suggests, HpCuMT has always been recovered from the snail tissue as a homometallic copper protein. In contrast, HpCdMT is induced in many cell types in snails exposed to cadmium, and is recovered as a homometallic cadmium protein.To find out whether the metals acquired by these proteins are due to the differential availability of the two metals at the site of synthesis of the metallothioneins or due to the inherent properties of the proteins, Palacios et al. expressed the two metallothioneins in Escherichia coli and yeast cells under conditions of varying metal exposure. In the presence of elevated copper and low oxygen, they recovered HpCuMT from E. coli as a homometallic copper protein whereas under the same conditions HpCdMT was recovered as a mixed species containing zinc (this protein is thought normally to buffer zinc but to bind cadmium after cadmium intoxication) as well as copper [3]. Conversely, when HpCdMT was expressed in E. coli enriched with either cadmium or zinc, homometallic, fully populated cadmium or zinc forms were recovered, although analogous expression of HpCuMT gave variable occupancy with cadmium or zinc [3]. The H. pomatia proteins also rescued sensitivity to cadmium or to copper in yeast mutants with metal sensitivities that matched the AbstractMetalloproteins are essential for many cellular functions, but it has not been clear how they distinguish between the different metals to bind the correct ones. A report in BMC Biology finds that preferences of two metallothionein isoforms for two different cations are due to inherent properties of these usually less discriminating proteins. Here these observations are discussed in the context of the cellular mechanisms that regulate metal binding to proteins.Promiscuity and preferences of metallothioneins: the cell rulesAndrew W Foster and Nigel J Robinson*See research article: http://www.biomedcentral.com/1741-7007/9/4CO M M E N TA RY  Open Access*Correspondence: nigel.robinson@durham.ac.uk Biophysical Sciences Institute, Department of Chemistry, School of Biological and Biomedical Sciences, Durham University, DH1 3LE, UK© 2011 Foster AW, Robinson NJ; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Foster AW, Robinson NJ BMC Biology 2011, 9:25http://www.biomedcentral.com/1741-7007/9/25metals selected by the respective metallothioneins. Retention of metal preferences in heterologous hosts argues that selectivity resides in the proteins. However, a heterologous environment still contains other proteins contributing to the buffering of metals, and these data do not necessarily mean, for example, that HpCdMT binds cadmium and/or zinc more tightly than copper. Rather, the data reflect the metal preferences of HpCdMT relative to other components of the mixed metal buffers of the organisms and cell types.What determines the metal preferences of proteins?Because proteins are flexible, they offer imperfect steric selection between metals. This is especially true of nascent proteins before folding. The affinities of proteins for metals are influenced by universal orders of preference, which for biologically essential divalent metals includes the Irving-Williams series (Figure 1a), which ranks the relative stability of complexes formed with each metal ion [4]. (Monovalent copper also forms tight associations with proteins, particularly when the ligands are cysteine thiolates, as in metallothioneins.) Several nonessential toxic metals, including mercury, cadmium and silver, also form tight complexes with thiolates, obeying an order of preference listed in Figure 1b [3]. Under the strictures of such affinity series how do large numbers of proteins become populated with less competitive metals such as magnesium and manganese, avoiding displacement by more tightly binding metals such as copper? Part of the answer is that the buffered concentrations of metals are controlled in cells in such a way that the most competitive metals are bound and buffered to the lowest available concentrations. This is illustrated by the predominant manganese protein and the predominant copper protein in the periplasm of a cyanobacterium [5]. These proteins, MncA and CucA, respectively, have identical sets of metal ligands and similar cupin folds. Moreover, the manganese protein MncA has a 10,000 times greater preference for the wrong metal, copper, than for manganese. However, whereas the copper protein folds after membrane translocation, MncA folds in the cytosol before translocation. Therefore, the cytosol must be a protected environment where the ratio of buffered copper to buffered manganese is less than 1:10,000, at least at the site where MncA folds. Once the protein has correctly enfolded manganese, the metal becomes kinetically entrapped and safe from replacement by more competitive metals such as copper [5]. The folding location thus overrides the metal-binding preference of MncA to dictate metal occupancy. Precise control of the ratios of buffered metals available to proteins at folding is thus crucial to ensure binding of the correct inorganic Figure 1. Universal orders of metal preference and proposed buffered metal concentrations in cells. (a) The Irving-Williams series provides a preferred binding order for divalent metals. (b) An order of preference for thiolate-containing ligands of some nonessential, and some essential, metals. (c) How the occupancy of HpCdMT and HpCuMT might relate to the buffered concentrations of metals in a hypothetical cell. The total concentration of each metal in a cell (squares) is many orders of magnitude greater than the buffered concentration (circles), with the exception of bulk solutes such as sodium and potassium. The values have been adapted from a proposal of da Silva and Williams [4]. Proteins with affinities tighter than the buffered concentrations can acquire metals. HpCuMT (green triangles) is suggested to have an affinity for copper slightly tighter than the buffered concentration of copper found in many cell types, whereas HpCdMT (red triangles) is suggested to have a copper affinity too weak to compete effectively with the copper buffers of at least some cell types. In this scheme the situation is reversed for zinc. There is evidence that the relationship between the H. pomatia metallothioneins and buffers for non-cognate metals depart from this scheme in some cell types.TightMg < Ca < Mn < Fe < Co < Ni < Cu > Zn(a)Na K Mg Ca Mn Fe Co Ni Cu ZntotalbufferedmillimicronanopicofemtomillimicronanopicofemtoHpCdMTHpCuMT(c)(b)Weak TightZn < Co < Pb < Cd < Cu / Ag < HgWeakMetal concentration (molar)Metal affinity (molar)Foster AW, Robinson NJ BMC Biology 2011, 9:25http://www.biomedcentral.com/1741-7007/9/25Page 2 of 3elements. Computational studies similarly conclude that in biological systems, in the absence of metallo-chaperones, the specificity of protein ligands for metals depends mainly on the local abundances of metals [6].Binding affinity, competition and control of metal availability in cellsThe availability of metals in cells is thought to be regulated by the actions of DNA-binding metal sensors that control the expression of genes encoding proteins of metal homeostasis, including metal-buffering proteins such as metallothioneins [1]. These sensors act to maintain the buffered concentrations of metals within limits determined, at least in part, by their own metal affinities [7]. Under such a regime the metal affinities of E. coli metal sensors will influence metal occupancy of snail metallothioneins when expressed in E. coli. The copper affinity of the E. coli copper sensor CueR, relative to the zinc affinities of the zinc sensors ZntR and Zur, suggests that copper is buffered to an even lower concentration than zinc [8,9] in E. coli. A protein is expected to gain access to a given metal only if the affinity of the protein for that metal is tighter than the buffered concentration. Thus, HpCuMT is predicted to have an affinity for copper tight enough to compete with other molecules that buffer copper in rhogocytes, and also in E.  coli and yeast. In contrast, HpCdMT is predicted to have an affinity for copper that is less able to compete with these other buffers (Figure 1c).Measurement of the absolute metal affinities of proteins has been surprisingly challenging, with many erroneous values in the literature [10]. The copper, cad-mium and zinc affinities of H. pomatia metallothioneins remain to be measured, but the scheme in Figure 1c suggests that HpCdMT and HpCuMT both have tighter affinities for copper than for cadmium or zinc, in accordance with the series in Figure 1a,b. Subtle differences between the two sequences must nonetheless give HpCuMT the tighter copper affinity of the two, as when both are expressed in the presence of excess copper in E. coli, only HpCuMT becomes fully populated with copper [3]. Notably, even after growth of E. coli in excess copper, recombinant HpCuMT was partly occupied with zinc unless the cells were also depleted of oxygen. Perhaps copper is buffered to a slightly lower concentration in aerobic E. coli than in rhogocytes, or perhaps the E. coli copper pool in aerobic conditions is swiftly depleted by overexpression of HpCuMT. There is no known demand for copper in the E. coli cytosol, although there is emerging evidence that periplasmic copper proteins are supplied with copper through export from the cytosol.It is hypothesized that the metals that occupy proteins and are critical to their function could be regulated according to cell type by adjusting the buffered metal concentrations to different settings in different cell types. HpCuMT itself contributes to the copper buffer in rhogocytes, implying that copper is buffered more tightly in these cells than in other cells, perhaps to withhold copper more effectively from metalloproteins other than hemocyanin. Technologies are being developed to measure the elusive availabilities of metals to nascent proteins. The mechanisms that maintain these buffered concentrations underlie much of biological catalysis.AcknowledgementsWork in the authors’ lab is supported by BBSRC research grants BB/H011110/2 and BB/H006052/1.Published: 28 April 2011References1. Waldron KJ, Rutherford JC, Ford D, Robinson NJ: Metalloproteins and metal sensing. Nature 2009, 460:823-830.2. Cvetkovic A, Menon AL, Thorgersen MP, Scott JW, Poole FL 2nd, Jenney FE Jr, Lancaster WA, Praissman JL, Shanmukh S, Vaccaro BJ, Trauger SA, Kalisiak E, Apon JV, Siuzdak G, Yannone SM, Tainer JA, Adams MW: Microbial metalloproteomes are largely uncharacterized. Nature 2010, 466:779-782.3. Palacios Ò, Pagani A, Pérez-Rafael S, Egg M, Höckner M, Brandstätter A, Capdevila M, Atrian S, Dallinger R: Shaping mechanisms of metal specificity in a family of metazoan metallothioneins: evolutionary differentiation of mollusc metallothioneins. BMC Biol 2011, 9:4.4. da Silva F, Williams RJP: The Biological Chemistry of the Elements: The Inorganic Chemistry of Life. 2nd edition. New York: Oxford University Press; 2001.5. Tottey S, Waldron KJ, Firbank SJ, Reale B, Bessant C, Sato K, Cheek TR, Gray J, Banfield MJ, Dennison C, Robinson NJ: Protein-folding location can regulate manganese-binding versus copper- or zinc-binding. Nature 2008, 455:1138-1142.6. Dudev T, Lim C: Metal binding affinity and selectivity in metalloproteins. Annu Rev Biophys 2008, 37:97-116.7. Helmann JD, Soonsanga S, Gabriel S: Metalloregulators: arbiters of metal sufficiency. Microbiol Monogr 2007, 6:37-71.8. Changela A, Chen K, Xue Y, Holschen J, Outten CE, O’Halloran TV, Mondragón A: Molecular basis of metal-ion selectivity and zeptomolar sensitivity by CueR. Science 2003, 301:1383-1387.9. Outten CE, O’Halloran TV: Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 2001, 292:2488-2492.10. Xiao Z, Wedd AG: The challenges of determining metal-protein affinities. Nat Prod Rep 2010, 27:768-789.Foster AW, Robinson NJ BMC Biology 2011, 9:25http://www.biomedcentral.com/1741-7007/9/25doi:10.1186/1741-7007-9-25Cite this article as: Foster AW, Robinson NJ: Promiscuity and preferences of metallothioneins: the cell rules. BMC Biology 2011, 9:25.Page 3 of 3

BMC Biology

Abstract Metalloproteins are essential for many cellular functions, but it has not been clear how they distinguish between the different metals to bind the correct ones. A report in BMC Biology finds that preferences of two metallothionein isoforms for two different cations are due to inherent properties of these usually less discriminating proteins. Here these observations are discussed in the context of the cellular mechanisms that regulate metal binding to proteins. See research article: http://www.biomedcentral.com/1741-7007/9/4</p

Robinson Nigel J

Foster Andrew W

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AG: The challenges of determining metal-protein affinities. Nat Prod Rep

Dallinger R: Shaping mechanisms of metal specificity in a family of metazoan metallothioneins: evolutionary differentiation of mollusc metallothioneins.

Lim C: Metal binding affinity and selectivity in metalloproteins. Annu Rev Biophys

Metalloregulators: arbiters of metal sufficiency. Microbiol Monogr

Mondragón A: Molecular basis of metal-ion selectivity and zeptomolar sensitivity by CueR. Science

MW: Microbial metalloproteomes are largely uncharacterized. Nature

NJ: Metalloproteins and metal sensing. Nature

NJ: Protein-folding location can regulate manganese-binding versus copper- or zinc-binding. Nature

O’Halloran TV: Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science

RJP: The Biological Chemistry of the Elements: The Inorganic Chemistry of Life. 2nd edition.

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Promiscuity and preferences of metallothioneins: the cell rules

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