Chemistry Reference
In-Depth Information
aggregate of PsP
Sc
(dark spheres). Seed formation is an extremely rare event: however, once a seed is present,
monomer addition ensues rapidly.
It has been well documented that the prion protein binds copper (II) ions and that, among divalent metal ions,
PsP
C
selectively binds Cu(II). The major copper(II)-binding site has been identified as being within the
unstructured amino terminal region (encompassing residues 60
91 of human PsP
C
). Specifically, copper binds to
a highly conserved octapeptide repeat domain, consisting of four sequential repeats of the sequence ProHis-
GlyGlyGlyTrpGlyAsn. The Cu(II) to octapeptide-binding stoichiometry is 1:1, i.e., the octapeptide repeat region
binds four Cu(II) ions, and copper binding is most favoured at physiological pH, falling off sharply under mildly
acidic conditions. While most studies of copper binding have focused on the octarepeat region, evidence has been
found for a fifth preferential Cu(II) coordination site, between residues His96 and His111, outside of the octar-
epeat domain, with a nanomolar dissociation constant. Interestingly, circular dichroism studies show that copper
coordination is associated with a loss of irregular structure and an increase in beta-sheet conformation.
Evidence is also growing that PsP
C
plays an important role in copper homeostasis, in particular at the pre-
synaptic membrane; that it may be involved in triggering intracellular calcium signals; and that it may play
a neuroprotective role in response to copper and oxidative stress (
Figure 21.13
)
. Exposure of neuroblastoma cells to
e
Schematic representation of the physiological role of prion protein (PrP
c
) in copper homeostasis and redox signalling.
FIGURE 21.13
(From
