(588b) When Misbehaving Proteins Met Well-Behaved Proteins…

Self-assembly of intrinsically disordered polypeptides (IDP) imparts toxic biological effects depending on the size in over 20 neurodegenerative diseases. Unfortunately, our understanding of amyloid polypeptides, as related to biomedical implications, is limited by their self-assembling nature. In this talk, I will first present our study on the creation of a dual peptide system, where a pair of β-amyloid (Aβ) variants, KLVFWAK and ELVFWAE, are not self-assembled but hetero-assembled in the presence of their assembly partners. We provide evidence that the resulting hetero-assemblies share molecular, structural and morphological similarities with typical amyloid self-assemblies formed by a single polypeptide (e.g., Aβ). We anticipate that our dual peptide system may readily be adapted for precise control of amyloid assembly, for the study of size-dependent neurotoxicity.

Unlike an IDP, a globular protein folds into a compact structure, responsible for various biological functions. Interestingly, globular proteins are also known to form amyloid fibrils under partially denaturing conditions, demonstrating that amyloid aggregation is a generic property of proteins. In the second half of this talk, I will present our study where a globular protein, Bacillus circulans xylanase (BCX), can aggregate to form amyloid fibrils under native conditions. Interestingly, addition of KLVFWAK or ELVFWAE modulated the BCX amyloid aggregation. This study also provides insight into a correlation between the kinetic stability and amyloid aggregation of BCX, and supports a view that Aβ-derived fragments can be useful for the modulating amyloid aggregation of some, though not all, globular proteins.