The World of Functional Amyloid - The Functional Fold: Amyloid Structures in Nature - page 5

monomer addition events, including dimerizations, are energetically
favourable (Fig. 1.2b). Many additional mechanistic paradigms will
likely be discovered; one example is the recently described nucleated
conformational conversion mechanism.

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Many, if not most, proteins can form amyloid under modestly
denaturing conditions

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suggesting that amyloid is a widely
accessible, low-energy protein quaternary structure derived from
partly denatured states. Amino acid composition can bias a given
polypeptide towards amyloid formation. Hydrophobic sequences
with a paucity of charge are particularly amyloidogenic, although
the specific sequence determinants for amyloid formation remain
poorly understood.

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Figure 1.2 Amyloid formation can occur by many mechanisms, two of

which are illustrated here. (a) In a nucleated polymerization,
monomer assembly into a high-energy oligomeric nucleus
is rate-limiting, with rapid polymerization to form fibres
after nucleus formation. (b) In a downhill polymerization,
all oligomerization steps are energetically favourable. The
biophysical characteristics of a polypeptide dictate, in part,
what mechanism will be observed. Conditions such as peptide
concentration and solution composition can also modulate the
mechanism. Our understanding of amyloidogenesis

is
poor; alternate mechanisms, influenced by chaperones and for
example, are likely to be found.

in vivo