Delineating the Role of Helical Intermediates in Natively Unfolded Polypeptide Amyloid Assembly and Cytotoxicity

Abstract

Amyloid deposition is a hallmark of many diseases, such as the Alzheimer's disease. Numerous amyloidogenic proteins, including the islet amyloid polypeptide (IAPP) associated with type II diabetes, are natively unfolded and need to undergo conformational rearrangements allowing the formation of locally ordered structure(s) to initiate self-assembly. Recent studies have indicated that the formation of α-helical intermediates accelerates fibrillization, suggesting that these species are on-pathway to amyloid assembly. By identifying an IAPP derivative with a restricted conformational ensemble that co-assembles with IAPP, we observed that helical species were off-pathway in homogenous environment and in presence of lipid bilayers or glycosaminoglycans. Moreover, preventing helical folding potentiated membrane perturbation and IAPP cytotoxicity, indicating that stabilization of helical motif(s) is a promising strategy to prevent cell degeneration associated with amyloidogenesis.

All‐atom structure ensembles of islet amyloid polypeptides determined by enhanced sampling and experiment data restraints

“…There is still great debate on the above models and neither of them can interpret all experiment observations. For instance, a recent study showed that the hIAPP with D‐residues (D‐hIAPP) at positions 15 and 16 have equivalent kinetics of self‐assembly with the wild‐type hIAPP . Since the D‐residues could prevent the N‐terminal α‐helical folding, this study demonstrated the N‐terminal helix formation is irrelevant to the aggregation .…”

Non-covalent S⋯O interactions control conformation in a scaffold that disrupts islet amyloid polypeptide fibrillation

“…4B). 40,41 The stabilisation of these membrane-bound α-helical states attenuates the formation of IAPP fibrils 41 and, as recent evidence suggests, decreases the cellular toxicity of IAPP. 41,42 This indicates therapeutic applications of IAPP helix stabilisers.…”

“…40,41 The stabilisation of these membrane-bound α-helical states attenuates the formation of IAPP fibrils 41 and, as recent evidence suggests, decreases the cellular toxicity of IAPP. 41,42 This indicates therapeutic applications of IAPP helix stabilisers. In our previous work, scaffolds functionalised with acidic, hydrophobic and acidic groups that overlay with positions i , i + 3/4 and i + 7 of an α-helix, respectively, were highly effective disruptors of membrane-catalysed IAPP fibrillation.…”

Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin

“…It does, however, diminish helicity 20 and cytotoxicity 21 . In contrast, a similarly motivated change in which residues 15 and 16 are replaced by D -amino acids diminishes helicity and yet increases cytotoxicity 22 . These contrasts suggest the presence and functional importance of molecular scale interactions.…”