A High “Steaks” Molecular Story: Copper Interactions with Mad Cow Disease Prion Proteins

Transmissible spongiform encephalopathies (TSEs), better known as prion diseases, are a group of progressive neurodegenerative diseases that affect both animals and humans. The most well‐known example, bovine spongiform encephalopathy (BSE), better known as “mad cow disease,” is a progressive neurological disorder of cattle that is created as a result of a mutation in the cellular prion protein (PrPc) into a toxic isoform called PrP scrapie (PrPSc). This disease first gained public attention when a British outbreak affected about 180,000 cattle between 1986 and 2001, devastating numerous agricultural communities. The Independent School BioClub SMART Team used 3‐D modeling and printing technology to examine PrPc and PrPSc molecular structures, focusing specifically on the protein’s metal‐binding properties. Copper (II) ion (Cu2+), PrPc’s highest affinity metal ion, plays a significant role in the interdomain interaction between the globular C‐terminal domain, consisting of three □‐helices and one short □‐sheet, and the flexible N‐terminal domain. Cu2+ ion binds to the PrPc N‐terminal octarepeat domain (OR), which is considered fundamental due to its series of four (or more) tandem repeats. Each tandem repeat can bind one Cu2+ ion, which directly interacts with a specific highly conserved, negatively‐charged region of the globular domain defined by the exposed surface of helices 2 and 3. The N‐terminal domain of PrPc causes severe neurotoxicity unless the globular domain properly regulates it. In humans, this prion protein mutation leads to Creutzfeldt‐Jakob disease (CJD), which has the same neurodegenerative symptoms as BSE. A negatively‐charged region on the surface of helix 3 occupied by the Cu2+ ion also overlaps with the epitopes of many PrPc antibodies associated with prion diseases. A better understanding of these interactions could potentially lead to discovering a cure for neurodegenerative diseases caused by PrPc’s misfolded form, such as CJD and Alzheimer’s.