Controllable membrane damage by tunable peptide aggregation with albumin

Abstract

Aggregation of otherwise soluble proteins into amyloid structures is a hallmark of many disorders, such as Alzheimers and Parkinsons diseases. There is increasing evidence and acceptance that instead of ordered amyloid assemblies, the misfolded oligomer aggregations are the main toxic structures. However, there is no system to study the mechanism and kinetics of aggregation, distinguish between ordered structures and misfolded oligomers, and correlate the structures to their toxicity. The exact role of oligomer aggregation in the pathological process remains to be elucidated. Here, we use an engineered co-assembling oppositely charged amyloid-like peptide pair ([II]) to relate its aggregation to toxicity. The toxicity mechanism of [II] is through cell membrane damage and stress, as shown with YAP and eIF2a; biomarkers, as in the amyloid protein-initiated diseases. Albumin is used to control the aggregation of [II], and so its toxicity. This study represents a molecular engineering strategy to study the aggregation process of amyloid-like structures in diseases. Understanding the nature of protein aggregation through engineered peptides paves the way for future designs and drug development applications.

Peptide aggregation-induced immunogenic cell death in a breast cancer spheroid model

“…Furthermore, we observed that PAIIR can trigger ICD and the release of DAMPs in various cell lines, leading to an enhanced immune response against the influenza vaccination model 18 . Notably, our research also unveiled that using albumin as a modulator can control both peptide aggregation on the cell membrane and their subsequent effects on ICD and DAMP release (Figure 1) 24 .…”

“…To induce ICD, we have developed a peptide-aggregation induced immunogenic response (PAIIR) method, which uses engineered peptides made of natural amino acids 19,20 . Inspired by the structures of transmembrane poreforming proteins [21][22][23] , we utilized our molecular framework 19 and designed a pair of oppositely charged peptides [II] that penetrate cells, aggregate, and induce stress and ICD 18,24 . Accumulation of misfolded proteins and their aggregates in the cells cause stress in the endoplasmic reticulum, and depending on the severity of the stress, it may stimulate eukaryote initiation factor 2 alpha (eIF2-) phosphorylation and calreticulin exposure, which are hallmark biomarkers of ICD 25 .…”