Hetero-oligomeric Amyloid Assembly and Mechanism: Prion Fragment PrP(106–126) Catalyzes the Islet Amyloid Polypeptide β-Hairpin

Abstract

Protein aggregation is typically attributed to the association of homologous amino acid sequences between monomers of the same protein. Coaggregation of heterogeneous peptide species can occur, however, and is implicated in the proliferation of seemingly unrelated protein diseases in the body. The prion protein fragment (PrP) and human islet amyloid polypeptide (hIAPP) serve as an interesting model of nonhomologous protein assembly as they coaggregate, despite a lack of sequence homology. We have applied ion-mobility mass spectrometry, atomic force microscopy, circular dichroism, and high-level molecular modeling to elucidate this important assembly process. We found that the prion fragment not only forms pervasive hetero-oligomeric aggregates with hIAPP but also promotes the transition of hIAPP into its amyloidogenic β-hairpin conformation. Further, when PrP was combined with non-amyloidogenic rIAPP, the two formed nearly identical hetero-oligomers to those seen with hIAPP, despite rIAPP containing β-sheet breaking proline substitutions. Additionally, while rIAPP does not natively form the amyloidogenic β-hairpin structure, it did so in the presence of PrP and underwent a conformational transition to β-sheet in solution. We also find that PrP forms hetero-oligomers with the IAPP fragment but not with the "aggregation hot spot" IAPP fragment. PrP apparently induces IAPP into a β-hairpin structure within the PrP:IAPP heterodimer complex and then, through ligand exchange, catalytically creates the amyloidogenic β-hairpin dimer of IAPP in significantly greater abundance than IAPP does on its own. This is a new mechanistic model that provides a critical foundation for the detailed study of hetero-oligomerization and prion-like proliferation in amyloid systems.

Unpacking the aggregation-oligomerization-fibrillization process of naturally-occurring hIAPP amyloid oligomers isolated directly from sera of children with obesity or diabetes mellitus

“…Biomarker identification of early β-cell failure is multidimensional and encompasses the need for a deep understanding of the aggregation/oligomerization process in vivo , their dynamics and their molecular networks 9 . We avoid the polymorphism of oligomeric species by concentrating on those oligomers with low molecular weight that are related to cellular apoptosis and may have a role to play in the developing stages of metabolic syndrome and diabetes 26,31,32,56,57 . We used a potential “universal pre-treatment”; which is cost-effective and easy to implement in diagnostic laboratories in hospitals 34 .…”

Review: PrP 106‐126 – 25 years after

“…Another area of research in which PrP106‐126 may prove useful is the investigation of hetero‐oligomeric structures. PrP106‐126 promoted the transition of human islet amyloid polypeptide into its amyloidogenic conformation . This approach might be applied to other misfolding proteins (e.g.…”

α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine

“…[5][6][7][8][9] The possible toxic species are not limited to oligomers of individual proteins but cross-seeding of several distinct species. [10][11][12][13] Thus, it is important to account for the intervention of molecules present in the same environment and how they possibly affect the aggregation. When two peptides co-assemble, the new system may acquire unique properties that neither homologous counterparts could have, including cytotoxicity and/or aggressive brillization, 10,14,15 which can contribute to or exacerbate disease pathology.…”