Functional amyloid and nonfunctional interpretations
Fowler et al. report results of studies of the biophysical behavior of
the
bovine melanosome protein Pmel17 and of the potential role of this protein in melanin biosynthesis. The data strongly support the conclusion that Pmel17, under appropriate conditions, rapidly assembles into amyloid-type polymers and that these polymers support melanin synthesis. The demonstration of a
physiologically beneficial role of Pmel17 amyloid adds another example
to a growing list of prokaryotic and eukaryotic proteins for which
amyloid formation serves an important role in normal cellular
function. In some respects, however, the authors' view of the
relative importance of these findings to larger questions of
prokaryotic and eukaryotic cell biology and the role of amyloid is
unsupported experimentally and thus must be considered
"nonfunctional."
One of the most interesting observations of Fowler et al. was the rate
of amyloid formation by Pmel17 (a half-time of roughly 1 second). This
rate was four orders of magnitude...
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Functional amyloid and nonfunctional interpretations
Fowler et al. report results of studies of the biophysical behavior of
the
bovine melanosome protein Pmel17 and of the potential role of this protein in melanin biosynthesis. The data strongly support the conclusion that Pmel17, under appropriate conditions, rapidly assembles into amyloid-type polymers and that these polymers support melanin synthesis. The demonstration of a
physiologically beneficial role of Pmel17 amyloid adds another example
to a growing list of prokaryotic and eukaryotic proteins for which
amyloid formation serves an important role in normal cellular
function. In some respects, however, the authors' view of the
relative importance of these findings to larger questions of
prokaryotic and eukaryotic cell biology and the role of amyloid is
unsupported experimentally and thus must be considered
"nonfunctional."
One of the most interesting observations of Fowler et al. was the rate
of amyloid formation by Pmel17 (a half-time of roughly 1 second). This
rate was four orders of magnitude larger than the rates observed for
the Alzheimer and Parkinson disease-linked proteins amyloid
β-protein and α-synuclein, respectively. This is a very
interesting and important result, because investigation of its
mechanistic basis has the potential to reveal structural factors
controlling amyloid formation not only by Pmel17 but also by many
others of the approximately 20 known amyloid proteins. The authors
suggest that this rate may be a result of evolutionary pressures to
minimize production of toxic intermediates in amyloid formation. This
may be so, but this teleological interpretation remains unsupported
experimentally.
This commentator is largely ignorant about melanosome biology, but one may postulate that factors other than "toxic intermediates" may have contributed with equal (or greater) importance to the protein evolution of Pmel17. For example, rapid assembly kinetics makes processes linked to Pmel17 assembly remarkably sensitive, and thus controllable, in temporal and
concentration "regimes." Also, because Pmel17 assembly occurs within a
specialized organelle—the early melanosome—any intermediates would
be sequestered from other cellular compartments that might be
sensitive to their toxic effects.
The high rate of Pmel17 assembly raises questions about how this
specific process can be integrated into the prevailing view that
amyloid proteins share a common core structural organization. How does
one reconcile a rate constant that is four orders of magnitude larger
than those of other amyloid proteins with a "common structure"? Do the
noncore regions of Pmel17 contribute to the population of the
amyloid-competent conformational state by the nascent, proteolytically
processed Pmel17 protein?
Studies of melanin biosynthesis in vitro suggest that Pmel17 amyloid
formation is linked to increased synthesis rates. The authors suggest
that this "is the first example of an amyloid that functions in a
chemical reaction." This may be so, but the argument would be
strengthened if greater mechanistic insight existed. The suggestion
that spatial organization of the substrate used in the experiments
(DHQ) might be involved is quite reasonable and lends itself to future
hypothesis testing.
I question the proposition that a "general name amyloidin" be
designated for "functional amyloid." Historically, terms have been
created to define new entities and this process has helped scientists
by standardizing meaning, facilitating communication and clarity of
thought. The authors have done a superb job of characterizing the
Pmel17 assembly product as amyloid, the classical fibrillar structure
defined by its dye-binding characteristics, secondary structure, x-ray
diffraction pattern, and morphology. Structurally, how does an
amyloidin differ from an amyloid? How do you distinguish amyloids
(which by definition have similar core structures) that have
beneficial or detrimental effects that are context (intracellular,
extracellular, or organ-specific milieu)-specific? This naming
exercise becomes a semantic endeavor with little benefit, creating
more obfuscation than clarification. How does one name a new amyloid
protein that in the future may be found to have a beneficial effect?
One would think initially that the protein is "nonfunctional" and
name it amyloid, when in fact it is an amyloidin under some
conditions. I suggest we maintain our current terminology and simply
define under what conditions specific amyloid proteins have beneficial
or detrimental physiologic effects.
View all comments by David Teplow
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I recommend this paper
