8WZX

Cryo-EM structure of the hamster prion 23-144 fibril at pH 3.7

Summary for 8WZX

• Entry DOI: 10.2210/pdb8wzx/pdb
• EMDB information: 37963
• Descriptor: Major prion protein (1 entity in total)
• Functional Keywords: prion, 23-144, hamster, prp, protein fibril
• Biological source: Mesocricetus auratus (golden hamster)
• Total number of polymer chains: 20
• Total formula weight: 247532.84

Authors

Lee, C.-H.,Saw, J.-E.,Chen, E.,Wang, C.-H.,Chen, R. (deposition date: 2023-11-02, release date: 2024-05-01, Last modification date: 2024-05-08)

Primary citation

Lee, C.H.,Saw, J.E.,Chen, E.H.,Wang, C.H.,Uchihashi, T.,Chen, R.P.
The Positively Charged Cluster in the N-terminal Disordered Region may Affect Prion Protein Misfolding: Cryo-EM Structure of Hamster PrP(23-144) Fibrils.
J.Mol.Biol., 436:168576-168576, 2024

PubMed Abstract: Prions, the misfolding form of prion proteins, are contagious proteinaceous macromolecules. Recent studies have shown that infectious prion fibrils formed in the brain and non-infectious fibrils formed from recombinant prion protein in a partially denaturing condition have distinct structures. The amyloid core of the in vitro-prepared non-infectious fibrils starts at about residue 160, while that of infectious prion fibrils formed in the brain involves a longer sequence (residues ∼90-230) of structural conversion. The C-terminal truncated prion protein PrP(23-144) can form infectious fibrils under certain conditions and cause disease in animals. In this study, we used cryogenic electron microscopy (cryo-EM) to resolve the structure of hamster sHaPrP(23-144) fibrils prepared at pH 3.7. This 2.88 Å cryo-EM structure has an amyloid core covering residues 94-144. It comprises two protofilaments, each containing five β-strands arranged as a long hairpin plus an N-terminal β-strand. This N-terminal β-strand resides in a positively charged cluster region (named PCC2; sequence 96-111), which interacts with the turn region of the opposite protofilaments' hairpin to stabilize the fibril structure. Interestingly, this sHaPrP(23-144) fibril structure differs from a recently reported structure formed by the human or mouse counterpart at pH 6.5. Moreover, sHaPrP(23-144) fibrils have many structural features in common with infectious prions. Whether this structure is infectious remains to be determined. More importantly, the sHaPrP(23-144) structure is different from the sHaPrP(108-144) fibrils prepared in the same fibrillization buffer, indicating that the N-terminal disordered region, possibly the positively charged cluster, influences the misfolding pathway of the prion protein.

PubMed: 38641239
DOI: 10.1016/j.jmb.2024.168576

Experimental method

ELECTRON MICROSCOPY (2.88 Å)