MINIREVIEW
Neuronal growth-inhibitory factor (metallothionein-3):
reactivity and structure of metal–thiolate clusters*
Peter Faller
1,2
1 CNRS, LCC (Laboratoire de Chimie de Coordination), Toulouse, France
2 Universite
´
de Toulouse, UPS, INPT; LCC; Toulouse, France
Introduction
Metallothionin-3 (MT3) was originally dubbed neuro-
nal growth-inhibitory factor (GIF) [1] because of the
discovery that it is a factor in brain extract with the
ability to inhibit neuronal outgrowth. Moreover, MT3
or GIF was reported to be down-regulated in extract
from Alzheimer’s disease (AD) brain. Later on it
became clear that GIF belongs to the metallothionein
(MT) family based on its high cysteine and metal con-
tents. In mammals, the MT family consists of four dif-
ferent subfamilies designated MT1 to MT4 [2–4].
Mammalian MTs are composed of a single polypep-
tide chain of 61–68 residues. They are characterized by
a conserved array of 20 cysteines and the absence of
His and aromatic amino acids. MT3 contains 68
amino acids with 70% sequence identity to the MT1
and MT2 (MT1 ⁄ 2) isoforms. The MT3 sequence
contains two inserts: an acidic hexapeptide in the C-
terminal region and a Thr in position 5. Moreover, a
conserved Cys-Pro-Cys-Pro motif between positions 6
and 9 is unique to MT3 [1,4,5].
All mammalian MTs can bind a variety of different

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*This article is dedicated to Prof. M. Vasak
on the occasion of his retirement
(Received 3 December 2009, revised 4 May
2010, accepted 17 May 2010)
doi:10.1111/j.1742-4658.2010.07717.x
Metallothionein-3, also called neuronal growth-inhibitory factor, is one of
the four members of the mammalian metallothionein family, which in turn
belongs to the metallothionein, a class of ubiquitously occurring low-
molecular-weight cysteine- and metal-rich proteins containing metal–
thiolate clusters. Mammalian metallothioneins contain two metal–thiolate
clusters of the type M(II)
3
-Cys
9
and M(II)
4
-Cys
11
[or Cu(I)
4
-CysS
6-9
].
Although metallothionein-3 shares these metal clusters with the well-
characterized metallothionein-1 and metallothionein-2, it shows distinct bio-
logical, structural and chemical properties. This short review focuses on the
recent developments regarding the chemistry of the metal clusters in metal-

including five bridging and six terminal cysteines. All
seven divalent metals are bound in tetrahedral coordi-
nation (Fig. 1) [4]. The precise cluster structure of the
Cu(I)
X
-CysS
Y
moieties in mammalian MTs has not yet
been determined, and the only structure available is
from the Cu(I)
8
-Cys
10
cluster in yeast MT (Fig. 2) [6].
It is unlikely, however, that mammalian MTs contain
such a cluster. Spectroscopic experiments on mamma-
lian MT1 ⁄ 2 indicate that they contain Cu(I)
4
-CysS
6-9
,
Cu(I)
6
-CysS
9-11
or Cu(I)
3 ⁄ 4
-Zn
x
CysS

result in oxidation or derivatization of the cysteines
with subsequent metal release [4].
Although MT3 belongs to the MT family and hence
shares the unusual properties of their metal–thiolate
clusters, there are important differences between MT3
and the well-characterized MT1 ⁄ 2 [4]. Such chemical
and structural differences are probably important for the
biological roles of MT3, such as its growth-inhibitory
activity, the non-inducibility of its gene by diverse metal
ions and other compounds known to elicit the formation
of MT1 ⁄ 2, its predominant localization in the central
nervous system with an accumulation in zinc-enriched
neurons, and its possibility of being excreted into the
extracellular space [4,9,10]. Note, that the latter may not
be restricted to MT3 as evidence is accumulating that
MT1 ⁄ 2 also occurs extracellularly [4]. This is summa-
rized in Table 1 and discussed in more detail below.
Metal content of MT3
Initially, MT3 was isolated from human brain with a
metal content of four Cu(I) and three Zn(II) per MT3
Fig. 1. Scheme of the two metal–thiolate clusters containing
Zn ⁄ Cd in mammalian MT1 ⁄ 2. Left: four-metal cluster [M(II)
4
-Cys
11
]
localized in the C-terminal a-domain. Right: three-metal cluster
[M(II)
3
-Cys

astrocytes [3]
Primary structure 70% sequence identity 68 amino acids 61 amino acids
20 cysteines, same arrangements Acidic 6-amino-acid insert in the
C-terminal domain
Absence of 6-amino-acid and Thr
insert
Thr insert at position 4
Cys(6)-Pro-Cys-Pro(9) Cys(5)-Ser-Cys-Ala(8)
Metal content Binds without metal exposure Zn
and perhaps Cu. No
heterometallic Zn ⁄ Cu clusters
Isolated as a mixture of Cu and Zn
[1,11], but perhaps in vivo
predominantly Zn [13]
Isolated predominantly as Zn only
Zn binding 7 Zn(II) bound to 20 thiolates Additional specific (eighth)
Zn-binding site [30,31]
Similar overall apparent K
d
of Zn Cu
4
Zn
4
: 4.2 · 10
)12
M[32] Zn7:
1.6 · 10
)11
M [17]
Zn7: 3.2 · 10

site [30]
No specific additional sites [30]
Cd binding similar to Zn Cd
7
form less compact than Zn7
[26]
Similar compactness [26]
Similar overall apparent K
d
of Cd Cd
7
: 5.0 · 10
)15
M [17] Cd
7
: 1.4 · 10
)15
M [17]
More non-cooperative Cd binding
[17]
More cooperative Cd binding (at pH
7.4) [17]
Zn ⁄ Cd–thiolate
clusters
Cd ⁄ Zn
3
-CysS
9
in b-domain and
Cd ⁄ Zn

Reaction with NO Cysteine oxidation and Zn release Zn release is faster [38] Zn release is slower [38]
Reaction with
ROS
Cysteine-oxidation and Zn-release
rates relatively similar [38]
Reaction with Pt
compounds
Reaction with Cys, Pt bound to
Cys
Cisplatin and transplatin react
faster [36]
Cisplatin and transplatin react
slower [36]
Cu(I) binding Cooperative formation of Cu
4
-
CysS
x
[33,43] Further forms:
Cu
8
MT (two Cu
4
-CysS
x
clusters in
each domain) Cu
12
MT (Cu
6

Zn
4
MT-3 [32] formation of
Cu
4
Zn
3
MT-3 with disulfide
Not studied
K
d
of Cu(I) K
d
estimated to be 1 · 10
)19
M Stronger Cu(I) affinity? [35] Weaker Cu(I) affinity? [35]
Cu(II) binding to
Zn
7
-MT
MT binds Cu(II) after reduction to
Cu(I) through cysteine oxidation
Formation of Cu(I)
4
Zn
4
MT-3 with
two disulfide bridges [37]
Zn form not studied
P. Faller Metal–thiolate clusters in metallothionein-3

MT3 binds predominantly seven Zn(II) or Cd(II) ions
with overall apparent dissociation constants, at pH
7.4, of 1.6 · 10
)11
m and 5.0 · 10
)15
m, respectively
[17]. The three-metal cluster was less stable than the
four-metal cluster for Zn(II) and Cd(II) [18]. Initially,
information about the presence of two separate metal–
thiolate clusters came from spectroscopic studies and
comparison with other MTs of Zn(II)- and Cd(II)-
MT3, as well as their individual domains [12,19–22].
Precise structural data were obtained by NMR show-
ing a Cd(II)
4
-CysS
11
cluster in the C-terminal domain
with Cd(II)-Cys connectivities identical to those found
in the structure of human MT2 [23,24]. Such informa-
tion is still lacking for the N-terminal cluster, but
molecular dynamics simulation proposed a Cd(II)
3
-
CysS
9
cluster structure essentially identical to that of
MT2 [9,25]. Thus, apart from determining the Cd(II)
3

9
in the
113
Cd(II) NMR were much less intense than those of
Cd(II)
4
-CysS
11
. Increasing the temperature did sharpen
them but their intensity was not enhanced [27].
Recently, Wang et al. [24] confirmed the low intensity
of the resonances of Cd(II)
3
-CysS
9
, although their dif-
ference from those of Cd(II)
4
-CysS
11
was smaller.
Moreover, NMR measurements of mouse MT3 and
human MT confirmed a high dynamical structure
caused by rapid internal motion (mostly of the first 12
amino acids) [24] and this was viewed as conforma-
tional exchange broadening. This dynamic structure,
only observed in the Cd(II)
3
-CysS
9

Cd(II) do not bind cooperatively to MT3 at pH 7.3.
Upon adding seven equivalents of Cd(II) or Zn(II) to
MT3, distributions of metal loading were detected,
ranging from five to nine for Cd(II) and from six to
eight for Zn(II) (note that identical experiments with
MT1A showed more homogeneous M(II)-binding of
seven metals per MT [30]). This would mean
that Cd(II)
7
-MT3, and, to a lesser extent, also Zn(II)
7
-
MT3, are heterogeneous in their metal content,
and that metal-exchange reactions between different
metal-loaded forms could be the reason for the higher
dynamics detected in NMR. However, this conclusion
has its limits, first because the MS analysis is not
quantitative and, second, because more recent MS
Metal–thiolate clusters in metallothionein-3 P. Faller
2924 FEBS Journal 277 (2010) 2921–2930 Journal compilation ª 2010 FEBS. No claim to original French government works
measurements did not confirm binding of more than
eight equivalents of Zn(II) [31]. Importantly, the bind-
ing of the eighth metal ion was confirmed by other
methods and studied in more detail. [31] An additional
equivalent of Zn(II) can bind to Zn(II)
7
-MT3 [but not
to Zn(II)
7
-MT2] with an apparent K

ity of the Cd(II)
3
-CysS
9
cluster. This is supported by
the almost complete loss of resonance intensity upon
binding of an additional Cd(II).
Disulfide bond formation might be another way to
produce heterogeneity and ⁄ or increased structural
dynamics in the b-domain, leading to partial disulfide
bonds and ⁄ or to disulfide exchange reactions, respec-
tively. No evidence for disulfide bond formation in
Zn(II)
7
-MT3 has been reported. Nevertheless, it might
be worthwhile to re-investigate this point because
oxidation of cysteine was noted in the Zn(II)
4
-CysS
11
cluster of freshly prepared Cu(I)
4
Zn(II)
4
-MT3 [32].
Definitive studies will be important to explore the
isostuctural replacement of Zn(II) with Cd(II), by
monitoring the peptide structure and the flexibility of
Zn(II) and Cd(II) by NMR spectroscopy. Another
interesting (and to my knowledge not yet reported)

Binding of Cu(I) to MT-3
The spectroscopic characterization of MT3 isolated
from bovine and equine brain showed that Cu is
bound in the oxidation state I in a four Cu(I)–thiolate
cluster, Cu(I)
4
-CysS
X
[12,20]. Furthermore, reconstitu-
tion experiments with human apo-T3 and its separate
domains reproduced closely the features of the isolated
native MT3 forms (bovine, equine) [32,33]. Moreover,
titration experiments of Cu(I) to apo-T3 (or to apo-
a- and apo-b-domains) showed cooperative formation
of the Cu–thiolate cluster involving eight or nine cyste-
ines [i.e. Cu(I)
4
-CysS
8-9
] [21,22,33]. In apo-T3 the first
cluster formed, Cu(I)
4
-CysS
8-9
, was localized in the
N-terminal domain [33]. The structure of this Cu(I)
4
-
CysS
8-9

Cu(I)
6
-CysS
11
in the N-terminal and C-terminal
domains, respectively [33].
The dissociation constant of Cu(I) to MT3 has not
been measured, but by analogy with other MTs it can
be estimated to be around 10
)19
m [34]. Judged from
the higher reactivity of Cu(I)-MT1 with 5,5¢-dithio-
bis(2-nitrobenzoic acid) (DTNB) compared with Cu(I)-
MT3, it has been proposed that the affinity of MT3
for Cu(I) is higher than that of MT1 ⁄ 2 [35]. One of
the remarkable features of Cu(I)
4
-CysS
8-9
clusters in
the isolated Cu(I)
4
-Zn
3-4
MT-3 is its stability in air.
P. Faller Metal–thiolate clusters in metallothionein-3
FEBS Journal 277 (2010) 2921–2930 Journal compilation ª 2010 FEBS. No claim to original French government works 2925
The spectroscopic features of isolated Cu(I)
4
-Zn

4
cluster is not known. Cu(I)–thiolates are
normally oxidized by molecular oxygen, resulting in
the formation of disulfide bonds (Eqn 1). Thiyl radi-
cals have been observed as an intermediate. The mech-
anism might be oxidation of Cu(I) by oxygen (Eqn 2).
The formed superoxide might oxidize a further equiva-
lent of Cu(I) (Eqn 3). A two-electron reaction of Cu(I)
with oxygen yielding H
2
O
2
is probably favored (Eqn
4) as the reduction of O
2
to O
2
•)
is thermodynamically
unfavored, but the two-electron oxidation of O
2
to
H
2
O
2
is favored.
2CuðIÞþ2S
À
þ O

O
2
ð4Þ
CuðIIÞÀS
À
! CuðIÞÀS

ð5Þ
2S

! S À S ð6Þ
Then, Cu(II) can oxidize thiolate to thiyl (Eqn 5)
and two thiyls form a disulfide bridge (Eqn 6). [It is
also possible for S
•
to react with a neighboring thiolate
to yield a disulfide radical anion (S-S
•)
), which can be
further oxidized to disulfide]. In the framework of this
mechanism several possibilities can be envisaged to
explain the air-stability of Cu(I)
4
-Zn
4
MT. The first
possibility is no accessibility of oxygen to the cluster.
This is unlikely because MT3 is more dynamic and
hence more exposed to the solvent. The second possi-
bility is steric hindrance to form disulfide bridges, and

tonation at physiological pH, yielding Zn–thiolate
complexes. This renders thiolates more nucleophilic
than thiols. However, their binding to Zn(II) generally
also inhibits the formation of disulfides under aerobic
conditions. The latter occurs with uncoordinated thio-
lates. Thus, Zn(II) binding elicits the formation of
thiolates, which are more reactive than thiols, but less
reactive than uncoordinated thiolates. This can be con-
sidered as the sulfur reactivity of MT on a biological
time scale is controled by the Zn-binding state. Thiols
would react too slowly, whereas free thiolates would
react too fast and be difficult to control.
Metal-centered reactions of MT3
In the framework of considering thiolates as simple
metal ligands, metal-exchange reactions such as Cd(II)
or Hg(II) with Zn(II)-MT have been studied with
MT1 ⁄ 2. However, as MT3 synthesis is not inducible
by exposure to metal ions, a role in detoxification is
less likely, which is probably the reason why metal-
exchange reactions with Cd(II), Hg(II), Pb(II), etc.,
have not been studied so far. Moreover, the interac-
tion of Zn(II)
7
MT3 with biologically relevant Cu(I)
has not been reported. By contrast, the reaction of
MT3 with cis-amminedichloridoplatinum(II) (cisplatin)
and trans-amminedichloridoplatinum(II) (transplatin)
has been studied. These reactions are of interest
because MTs play an important role in the acquired
Metal–thiolate clusters in metallothionein-3 P. Faller

is
cooperative, forming a Cu(I)
4
–thiolate cluster in the
N-terminal domain of Cu(I)
4
,Zn(II)
4
MT3 together
with two disulfide bonds. Because four zinc ions
remain bound, it seems likely that the four-metal Zn
4
–
thiolate cluster in the a-domain stayed intact. As a
consequence the two disulfides would be localized in
the b-domain with the Cu(I)
4
–thiolate cluster. The
formed Cu(I)
4
–thiolate cluster has spectroscopic prop-
erties similar to the isolated and the Cu(I)-reconsti-
tuted Cu(I)
4
Zn(II)
4
MT3 described above, including
stability in air. The reaction of Zn(II)
7
MT3 with

scavengers and in the
conversion of a NO
•
signal to a Zn(II) signal. The
reaction with NO
•
providing S-nitrosothiols is sug-
gested to be a transnitrosation (i.e. translocation of
NO
+
from the S-nitrosothiols to the cysteine of MT),
which then releases NO
)
during the formation of disul-
fides [38]. This means that NO
)
is not stable in the
MTs and a storage function of MTs for NO· is less
likely. By comparing the reaction of NO and S-nitros-
othiols in MT3 and MT1 ⁄ 2, Chen et al. [38] found
that MT3 was much more reactive, whereas the activi-
ties with reactive oxygen species (H
2
O
2
, OCl
)
,O
2
•)

metal-loaded form [19].
In general, it can be suggested that MT3 is more
reactive than MT1 ⁄ 2, which is probably related to its
more flexible b-domain and hence to a better access of
compounds to the metal–thiolate cluster. This is also
in line with the general (but not exclusive) observation
that the difference in reactivity is more pronounced for
larger molecules (DTNB, providing S-nitrosothiols)
than for small molecules (H
2
O
2
, OCl
)
,O
2
•)
).
Conclusions and Perspectives
MT3 is clearly a member of the MT family as it shares
with them several biological and chemical properties;
however, there are also very distinct chemical features
that might be directly relevant to the particular biolog-
ical properties of MT3. Therefore, comparison of the
properties of MT3 with those of the well-studied
P. Faller Metal–thiolate clusters in metallothionein-3
FEBS Journal 277 (2010) 2921–2930 Journal compilation ª 2010 FEBS. No claim to original French government works 2927
MT1 ⁄ 2 forms could yield information on the structural
and chemical features responsible for the biological
peculiarities of MT3, such as its growth-inhibitory

Although the question of whether Cu(I) is physio-
logically bound to MT3 is not as yet resolved (see ear-
lier), it is clear that MT3 has the capacity of binding
Cu(I) under conditions of Cu-homeostasis breakdown.
There are several unanswered questions concerning
Cu(I)MT3. First the exact cluster structures of the dif-
ferent forms are not known [i.e. Cu(I)
4
,Zn(II)
4
MT3
(with or without disulfides), Cu(I)
4
,Cu(I)
4
MT3 and
Cu(I)
6
,Cu(I)
6
MT3]. The determination of a 3D struc-
ture seems crucial for understanding the differences
between Cu–MT3 and Cu–MT1 ⁄ 2 (structure also not
known) and the presence and role of the disulfide
bonds. This would also give insight into the stability
of the Cu(I)
4
-CysS
X
cluster in the b-domain of MT3

cluster are very similar to those of the
reconstituted forms. One partial explanation would be
that the spectroscopic features of the Cu(I)
4
cluster are
not affected by the presence of disulfide bridges and
this cluster is only stable in air in the presence of one
or two disulfide bonds. This could explain the sensitiv-
ity to oxidation of freshly reconstituted Cu(I)
4
,
Zn(II)
4
MT3 and the stability of Cu(I)
4
,
Zn(II)
4
MT3 [isolated, incubated or generated upon
Cu(II) binding] in air. However, this does not explain
why the disulfide bridge is formed in the a-domain
(instead of the b-domain) upon oxidation of freshly
reconstituted Cu(I)
4
,Zn(II)
4
MT3. To shed more light
on this issue it might be worthwhile investigating the
number and localization of disulfide bridges in diverse
preparations of MT3.

cysteine oxidation ⁄ modification, by protonation or by
protein breakdown. If the Cu(I) transfer did not taking
place, MT would just be a sink for Cu(I). This could
be sufficient for a redox-silencing role of MT3 for Cu.
In this context it might be interesting to search for
possible binding partners of Cu(I)
4
MT3.
Since the discovery of MT3 [1] almost 20 years ago,
it has been discovered that this member of the family
has unusual biological and chemical properties, clearly
distinct from the widely expressed MT1 ⁄ 2. This holds
also for structure and reactivity of the metal–thiolate
clusters, in particular for the cluster in the b-domain.
Metal–thiolate clusters in metallothionein-3 P. Faller
2928 FEBS Journal 277 (2010) 2921–2930 Journal compilation ª 2010 FEBS. No claim to original French government works
Several intriguing facets have been observed, such as
high dynamics, formation of disulfides, high reactivity,
stability of the Cu(I)
4
-cluster, etc. A better understand-
ing of these features will help to shed light on the
specific biological roles of MT3.
Acknowledgement
Gabriele Meloni (Caltech, USA) and Milan Vasak
(Univ. Zu
¨
rich) are acknowledged for very helpful
discussion.
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