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important in this context, as many proteins require metal ion(s) for their optimal structure
and function.
1.2 Metalloproteins
1.2.1 Metalloproteins are Nature's “Metallofoldamers!”
The term “foldamer” was defined as “polymers with a strong tendency to adopt a specific
compact conformation” (Gellman) or “oligomers that fold into a conformationally
ordered state in solution, the structures of which are stabilized by a collection of noncova-
lent interactions between nonadjacent monomer units” (Moore) [1]. In this respect fol-
damers share common characteristic with proteins and thus the term is adopted to
differentiate synthetic oligomers and polymers from “nature's foldamers” such as pep-
tides, proteins, and nucleic acids. The term “metallofoldamers” thus is used to describe
foldamers that adopt conformationally ordered states in the presence of metal ions or
complexes [2]. Therein, the metal center(s) plays a key structural role in the formation of
the specific conformation of the corresponding foldamer.
Metal ions may play a key role in the conformational changes of proteins or pep-
tides crucial in their functions. Given the high occurrence of metal ions as cofactors
and their integral role in the function of proteins in carrying out catalytic transforma-
tions, it is important to review how they are incorporated in the structure of proteins.
The mechanism of metal incorporation ranges from a controlled manner through the
use of metallochaperones to the direct incorporation from the cellular pool. In the
former case this specific class of proteins binds metal ions and mediates the delivery
into target enzymes through protein-protein interactions. In the case of iron transport
and heme incorporation, transferrin transports iron into cells and hemopexin delivers
apo-heme to the same compartment. For cytochrome-c, the heme must be attached
before proper folding occurs [3], whereas the assembly of Fe-S clusters and incorpo-
ration into proteins and the folding of the F-S proteins require machinery encoded in
the iron-sulfur cluster operon [4].
Nevertheless, metal ion incorporation is not always well controlled in such a man-
ner. There are still many metalloproteins without a known chaperone counterpart for
metal delivery and folding. Therefore, metal incorporation has also been suggested
to be controlled by the choice of compartment in which the metal incorporation
takes place. From studies in cyanobacteria, it becomes apparent that many copper
and manganese containing proteins fold in different compartments where metal
insertion can be controlled in a way that the Irvin-Williams series of stability can be
circumvented [5].
A classic example of the structural role of metal ions that affects the function is the zinc
finger domains, wherein the metal ions crosslink a-b domains and thus play a central role
in the formation of the defined structures. The metal binding as well as the packing of a
hydrophobic core drive the folding process. The zinc coordinates to the Cys
2
His
2
motif and
drives the folding process, while its removal causes the disruption of the proper folding.
These zinc finger domains were first found in the transcription factor TFIIIA, which repre-
sents the most common nucleic acid binding motif in transcription factors [6]. Upon bind-
ing to DNA, the Zn finger domains undergo further conformational change in order to fit
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