Mammalian Functional Amyloid - The Functional Fold: Amyloid Structures in Nature - page 151

α

The function of M amyloid within the melanosome appears

to be to template and accelerate the chemical synthesis of melanin
(Fig. 9.3). Recombinant M

derived from
biological sources, accelerate the polymerization of small molecule
melanogenic precursors such as 5,6-indolequinone into melanin
in vitro

α

fibres, as well as M

α

5,6,9

amyloid
likely reduces the entropic requirements for melanin formation by
increasing the effective 5,6-indolequinone concentration and by
orienting 5,6-indolequinone monomers along the M

. Binding 5,6-indolequinone molecules to M

α

fibre. Amyloid
fibres derived from other amyloidogenic polypeptides, such as
α

α

β

, afford an equal rate enhancement, whereas
protein fibres that do not have a cross-

-synuclein and A

β

-sheet structure, such as
collagen, do not enhance melanin synthesis.

5

These data indicate
that the amyloid structure itself is responsible for enhancing the
melanin polymerization rate. Thus, M

α

amyloid fibres have a clear
function within the melanosome, increasing the rate of melanin
formation by acting as a multivalent template for 5,6-indolequinone
polymerization (Fig. 9.3).

allele encodes variant of the Pmel17 protein that lacks
the cytoplasmic portion of the protein, presumably preventing
trafficking from the endoplasmic reticulum to the melanosome.
Thus, melanosomes in

The si

α

fibres. Curiously,
they are still able to generate melanin owing to the oxidation and
polymerization of melanogenic precursor compounds within the
melanosome. However,

si / si mice do not form M

individuals suffer from a progressive
loss of melanocytes and cultured

si / si

si / si melanocytes grow more

slowly than wild-type melanocytes.

6

These data suggest that M

α

amyloid fibres function in protecting melanocytes from the toxic
side effects of generating melanin. Melanin precursors including
5,6-indolequinone are extremely cytotoxic; these compounds
are potent oxidizers that can react both as electrophiles and
nucleophiles.

10

Furthermore, their low charge density makes
them likely to diffuse easily across the melanosomal membrane
into the cytosol. Such leakage explains the progressive melanocyte
destruction observed in the

α

amyloid
appears to bind and sequester reactive melanogenic intermediates,
preventing their diffusion out of the melanosome (Fig. 9.4).

si / si animals. Therefore, M