Loss of Residues 119-136, Including the First b-strand of Human Prion Protein, Generates an Aggregation-competent Partially Open Form

In prion replication, the cellular form of prion protein (PrPC) must undergo a full conformational transition to its disease-associated fibrillar form. Transmembrane forms of PrP have been implicated in this structural conversion. The cooperative unfolding of a structural core in PrPC presents a substantial energy barrier to prion formation, with membrane insertion and detachment of parts of PrP presenting a plausible route to its reduction. Here, we examined the removal of residues 119-136 of PrP, a region which includes the first b-strand and a substantial portion of the conserved hydrophobic region of PrP, a region which associates with the ER membrane, on the structure, stability and self-association of the folded domain of PrPC. We see an open native-like conformer with increased solvent exposure which fibrilises more readily than the native state. These data suggest a stepwise folding transition, which is initiated by the conformational switch to this open form of PrPC.& COPY; 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecom-mons.org/licenses/by/4.0/).

Automated summary

In prion replication, the conversion of cellular form of prion protein (PrPC) to its disease-associated fibrillar form is achieved through a full conformational transition. Transmembrane forms of PrP play a role in this structural conversion. Removing residues 119-136 of PrP, which includes the first β-strand and a large portion of the conserved hydrophobic region associated with the ER membrane, resulted in an open native-like conformer of PrPC with increased solvent exposure and enhanced fibril formation. These findings suggest a stepwise folding transition initiated by the conformational switch to this open form of PrPC.