Cross-Seeding of Fibrils
from Two Types of Insulin
Induces New Amyloid Strains
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Abstract
The irreversibility and autocatalytic character of amyloidogenesis
and the polymorphism of amyloid fibrils underlie the phenomenon of
self-propagating strains, wherein the mother seed, rather than the
seeding environment, determines the properties of daughter fibrils.
Here we study the formation of amyloid fibrils from bovine insulin
and the recombinant Lys<sup>B31</sup>-Arg<sup>B32</sup> human insulin
analog. The two polypeptides are similar enough to cross-seed but,
upon spontaneous aggregation, form amyloid fibrils with distinct spectral
features in the infrared amide I′ band region. When bovine
insulin is cross-seeded with the analog amyloid (and vice versa),
the shape, absorption maximum, and even fine fingerprint features
of the amide I′ band are passed from the mother to daughter
fibrils with a high degree of fidelity. Although the differences in
primary structure between bovine insulin and the Lys<sup>B31</sup>-Arg<sup>B32</sup> analog of human insulin lie outside of the polypeptide’s
critical amyloidogenic regions, they affect the secondary structure
of fibrils, possibly the formation of intermolecular salt bridges,
and the susceptibility to dissection and denaturation with dimethyl
sulfoxide (DMSO). All these phenotypic features of mother fibrils
are imprinted in daughter amyloid upon cross-seeding. Analysis of
noncooperative DMSO-induced denaturation of daughter fibrils suggests
that the self-propagating polymorphism underlying the emergence of
new amyloid strains is encoded on the level of secondary structure.
Our findings have been discussed in the context of polymorphism of
fibrils, amyloid strains, and possible implications for mechanisms
of amyloidogenesis