When abnormal forms of prion protein accumulate in the brain, spongiform encephalopathies, a group of fatal neurodegenerative diseases, may result. Prion protein (PrP) is thought to function in copper transport and cell signaling and is associated with cell membranes through a C-terminal glycolipid anchor. Prion protein (PrPC) may unfold and refold into an abnormal structure (PrPSc), leading to differing physical properties and function. PrPC folded in its wild type form is highly α-helical, while PrPSc contains more β-sheet structures that lead to misfolded non-functioning aggregates. These differing structures result in their differing characteristics; PrPC is easily degradable, while PrPSc is highly insoluble and demonstrates resistance to digestion. To investigate the role that lipid membranes have in this secondary structure conversion to PrPSc, a combination of calcein permeability assays, circular dichroism (CD) to monitor peptide secondary structure, and isothermal titration calorimetry (ITC) were performed on PrP(106-126), a short peptide fragment of PrP that recapitulates many of the known features of PrPSc, in conjunction with negatively charge small unilamellar vesicles, a model system for neuronal membranes. At physiologically relevant concentrations, monomeric PrP(106-126) does not cause an increase in membrane permeability or disruption. The lipid interface does induce significant secondary structure transformation of PrP(106-126), determined through fitting the CD with various models, which scales with concentration of negatively charged lipid, indicating that membrane composition affects the peptide-membrane binding mechanism. Additionally, results will be presented on the thermodynamic binding parameters upon addition of PrP(106-126) to model membranes and how the process is affected by membrane composition.

Interaction of PrP(106-126) with model cell membranes

ACS Spring Meeting 2021

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