A proteolytic functional amyloid digests pathogenic amyloids

Abstract

Although amyloids are a well-known pathological structure, functional amyloids are beneficial. Functional amyloids can be engineered to cultivate desired functionality that can destroy malicious amyloids. However, not much is known about such amyloid destructors. On the other hand, nearly all approaches to developing a drug against pathogenic amyloidoses have failed. Therefore, novel approaches are needed. Herein, a rationally designed catalytic triad based “proteolytic functional amyloid (PFA)” formed by linking a target protein recognizing unit with a Gly-integrated non-native Glu-His-Cys segment is reported. The proteolytic mechanism of the designed PFA is boosted by thiol/disulfide exchange cleavage. Rigorous MALDI-TOF and FRET-based analyses indicated that the PFAs cleaved Aβ12-21 (model Aβ) and the pathogenic Aβ1-40 site selectively in vitro. PFA significantly inhibited the aggregation of Aβ1-40 and broke-down the preformed fibrillar amyloids into non-toxic metabolites. Such a platform may be helpful in not only the on-demand chemical degradation of pathogenic amyloids but also the targeted degradation of other malicious proteins. PFAs are the first “amyloid-destroying” amyloids.