Different Folding States from the Same Protein Sequence Determine Reversible vs Irreversible Amyloid Fate

The propensity to self-assemble into amyloid fibrils with a shared cross-beta architecture is a generic feature of proteins. Amyloid-related diseases affect millions of people worldwide, yet they are incurable and cannot be effectively prevented, largely due to the irreversible assembly and extraordinary stability of amyloid fibrils. Recent studies suggest that labile amyloids may be possible in certain proteins containing low-complexity domains often involved in the formation of subcellular membraneless organelles. Although the fundamental understanding of this reversible amyloid folding process is completely missing, the current view is that a given protein sequence will result in either irreversible, as in most of the cases, or reversible amyloid fibrils, as in few exceptions. Here we show that two common globular proteins, human lysozyme and its homologue from hen egg white, can self-assemble into both reversible and irreversible amyloid fibrils depending on the folding path followed by the protein. In both folding states, the amyloid nature of the fibrils is demonstrated at the molecular level by its cross-beta structure, yet with substantial differences on the mesoscopic polymorphism and the labile nature of the amyloid state. Structural analysis shows that reversible and irreversible amyloid fibrils possess the same full-length protein sequence but different fibril core structures and beta-sheet arrangements. These results illuminate a mechanistic link between the reversible and irreversible nature of amyloids and highlight the central role of protein folding states in regulating the lability and reversibility of amyloids.

Automated summary

The propensity of proteins to self-assemble into amyloid fibrils with a shared cross-beta architecture is common, but the irreversibility and stability of amyloid fibrils make amyloid-related diseases difficult to treat. Recent studies suggest that certain proteins with low-complexity domains may form labile amyloids. Research shows that reversible and irreversible amyloid fibrils formed from the same full-length protein sequence have differences in core structures and beta-sheet arrangements, highlighting the role of protein folding states in regulating amyloid lability and reversibility.