Metalloproteins and Metallopeptides –Natural Metallofoldamers - Metallofoldamers: Supramolecular Architectures from Helicates to Biomimetics - page 22

Figure 1.15 (a) Structure of extended b-sheet Ab(17-42) from solid state NMR (PDB ID
2BEG). (b) Solution structure of helical Ab(1-28) in micelles by NMR (1AMB). (c) Crystal struc-
ture of human insulin-degrading enzyme with a bound Ab(1-42) of an extended structure,
showing one monomer in cyan (2WK3). (d, e) Stereo views of (d) Zn 2þ -bound Ab (1ZE9) and
(e) Co 2þ -bound Ab.
metal binding and/or the formation of aggregates and fibrils under different conditions can
be established, providing a good example of metallopeptides as natural metallofoldamers.
1.3.2.2 Prion Proteins and Fragments
The cellular form of prion protein PrP C (209 amino acids for the mammalian one) is a Cu 2þ -
binding glycoprotein which is attached to the cell surface via a glycosylphosphatidylinositol
anchor [201] and contains Cu 2þ when isolated from a diseased brain [202]. The C-terminal
domain of PrP C is mainly a-helical [203,204], whereas the N-terminal domain is
unstructured in the absence of Cu 2þ (Figure 1.16a, b) [205,206]. PrP C is converted into an
infectious form PrP Sc (scrapie isoform) when misfolded and aggregated (Figure 1.16c). This
is responsible for transmissible spongiform encephalopathies such as bovine spongiform
encephalopathy, ovine scrapie, and human Creutzfeldt-Jakob disease. Misfolding of PrP C
with three a-helices and a short anti-parallel b-sheet to afford the self-assembled oligomeric
b-sheet-rich PrP Sc is essential to the transmissible spongiform encephalopathies. Unlike the
disordered protein moieties which are integrated parts of protein structure and function com-
monly found in signaling and regulatory proteins that can induce/adopt certain conforma-
tions for specific interactions with targets [207], the misfolded PrP Sc can “infect” normal
PrP C and convert it into the disease-causing misfolded form. Recent studies on PrP C -knock-
out cells and on truncated PrP C devoid of the Cu 2þ -binding repeats pointed to a possible role
of this protein serving as a metal transporter [208]. Moreover, the Cu 2þ centers can generate
reactive oxygen species to cause oxidative stress in the brain [209] and can result in