Metalloproteins and Metallopeptides –Natural Metallofoldamers - Metallofoldamers: Supramolecular Architectures from Helicates to Biomimetics - page 24

form. In addition to the disease-causing mammalian prions, many fungal prions are also
known to undergo structural change to form amyloid filaments, which may be involved in
normal or diseased states, such as the prion-forming domain at residues 218-289 of the
HET-s protein from the filamentous fungus Podospora anserine [217] (Figure 1.16c).
These fungal prions may be involved in fungal epigenetic processes [218] and also serve
as good models systems for a better understanding of the structure and function of mam-
malian prions.

1.3.3 Other Metallopeptides

Peptide chains undergo dramatic conformational changes upon formation of secondary
structures, which can be triggered by metal binding or interacting with target molecules,
as discussed above. In addition to the natural metallopeptides discussed above, there are a
number of synthetic peptides that can also undergo similar conformational changes. Such
a structural property is applicable to the design of metallopeptides for further investiga-
tion of the structure and function of natural metallopeptides and metalloproteins and as
therapeutic agents. A couple examples are given here.

1.3.3.1 N-Terminal Binding Peptides and Ni-SOD

The N-terminal metal-binding site in serum albumin represents a typical coordination in
metallopeptides and is comprised of a large number of natural and synthetic peptides, as
in the case of histatin discussed above. Moreover, both the C- and N-termini of proteins
are the “loose ends” in protein folding and thus can significantly contribute to protein
stability when they are “tightened up” [219]. The binding of Cu 2þ to a deprotonated pep-
tidyl amide results in the formation of a square planar metal center and a change in con-
formation of the peptide, as in the case of Cu 2þ binding to the octarepeats in prion
discussed above [215]. A square planar geometry is also formed in several Cu 2þ com-
plexes of Tyr-containing peptides at elevated pH through a proposed binding to the N-
terminal amine and a deprotonated Gly-amide and binding to the phenolate of a Tyr side
chain by showing a charge transfer transition at 400 nm, such as the monomeric

[Cu II LH -1 ](L ¼ Phe-Gly-Pro-Tyr) complex and the dimeric [(CuLH -1 ) 2 ](L ¼ Tyr-Gly-

pH 8-10 on the basis of the distinct (O )Tyr to Cu 2þ charge

Pro-Phe) complexes at

transfer transitions at 400 nm [220]. Once again, the coordination sphere was proposed

based on spectroscopic features since the structures of these complexes were not solved.
Cu 2þ binding to a-synuclein may play a role in the fibrillogenesis of Parkinson's disease
[221]. Cu 2þ binds to the N-terminus Met-Asp of a-synuclein and folds this moiety into a
square planar geometry with the N-terminal amine, Asp-amido (H 1 ), and Asp-carboxyl-
ate as the ligands, along with His50 which may or may not be involved [222], and a disso-
ciation constant of 0.10 nM [222,223].
Another kind of N-terminal metal-binding site is found in Ni-containing superoxide
dismutase [224] (SOD; see Section 1.2.4 for a summary of this family of enzymes). The
Ni center undergoes redox cycle between Ni 2þ and Ni 3þ during the catalytic cycle,
accompanied by conformational change at the N-terminal Ni coordination sphere. The Ni
ion is bound to the N-terminus of the sequence His 1 - Cys 2 -Asp-Leu-Pro- Cys 6 of the pro-
tein through the N-terminal amine of His1, the peptidyl amido-N of Cys2, and the thio-
lates of Cys2 and Cys6 in the reduced Ni 2þ state with a square planar geometry, and an