Biology Reference
In-Depth Information
Amyloid formation can be deleterious in many contexts, so it is
interesting to note that several features of Pmel17 amyloidogenesis
seem designed to avoid toxicity. For example, the Pmel17 protein
has many features that prevent inappropriate fibre assembly. The
proteolytic cleavage of full-length Pmel17 that enables amyloid
formation by the lumenal M
α
fragment occurs in post-Golgi
compartments that go on to become melanosomes
7
(Fig. 9.2).
Because full-length Pmel17 is incapable of forming fibres,
8
cellular
compartments upstream of the melanosome, such as the ER and Golgi,
are protected from aberrant M
α
assembly. After proteolytic cleavage,
α
M
remains joined by a disulfide bond to the transmembrane/
cytoplasmic fragment, M
7
This could serve as a second physical
barrier against improper assembly of M
β
.
α
α
. M
is likely then released
from the membrane when M
is degraded; this event initiates
amyloid formation. Finally, Pmel17 stability and processing appears
to be positively influenced by the melanosomal MART-1 protein,
β
14
suggesting that MART-1 may be a functional regulator of Pmel17
folding and amyloidogenesis.
In addition to an ornate system for preventing premature
aggregation, Pmel17 features extremely rapid amyloidogenesis that
could be important in avoiding amyloid-related toxicity. Soluble
amyloid oligomers appear to be highly toxic.
15
In particular, pore-like
amyloid oligomers that compromise membrane integrity have been
observed and are hypothesized to be the toxic species responsible for
cell and tissue damage in amyloid disease.
16
amyloid
oligomers could rupture the melanosomal membrane and cause
leakage of toxic melanogenic precursor compounds into the cytosol.
However, oligomeric species are not likely populated to any sig-
nificant extent during M
If formed, M
α
amyloidogenesis because it occurs at least
four orders of magnitude faster than pathological A
α
β
or
α
-synuclein
5
amyloid formation.
Extremely rapid amyloidogenesis, probably
the result of an energetically favourable downhill polymerization
would minimize the concentration of oligomers and thereby avoid
exposing the cell to this key toxic species. By endowing Pmel17 with
the ability to form amyloid so rapidly, evolution appears to have
circumvented one of the fundamental challenges facing functional
amyloid — the generation of toxic oligomeric intermediates. Further
study is required to understand the broader principles of regulation
of functional amyloidogenesis and the potential interplay between
functional and pathological amyloid.
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