The Positively Charged Cluster in the N-terminal Disordered Region may Affect Prion Protein Misfolding: Cryo-EM Structure of Hamster PrP(23-144) Fibrils

被引：0

作者：

Lee, Chih-Hsuan ^{[1
]}

Saw, Jing-Ee ^{[1
,2
]}

Chen, Eric H. -L. ^{[1
]}

Wang, Chun-Hsiung ^{[1
]}

Uchihashi, Takayuki ^{[3
,4
,5
]}

Chen, Rita P. -Y. ^{[1
,2
,6
,7
]}

机构：

[1] Acad Sinica, Inst Biol Chem, 128,Sec 2,Acad Rd, Taipei 115, Taiwan

[2] Natl Taiwan Univ, Inst Biochem Sci, 1,Sec 4,Roosevelt Rd, Taipei 106, Taiwan

[3] Nagoya Univ, Dept Phys, Nagoya 4648602, Japan

[4] Nagoya Univ, Inst Glycocore Res IGCORE, Nagoya 4648602, Japan

[5] Natl Inst Nat Sci, Exploratory Res Ctr Life & Living Syst ExCELLS, Okazaki, Aichi 4448787, Japan

[6] Acad Sinica, Neurosci Program, 128,Sec 2,Acad Rd, Taipei 115, Taiwan

[7] Inst Biol Chem, Acad Sinica, 128,Sec 2,Acad Rd, Taipei 11529, Taiwan

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2024年 / 436卷 / 11期

关键词：

prion; cryoEM; amyloid fibril; protein misfolding; hamster; AMYLOID FIBRILS; CONVERSION; CONFORMATION; SPECIFICITY; PARALLEL; DOMAIN; MICE;

D O I：

10.1016/j.jmb.2024.168576

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 similar to 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 angstrom cryo-EM structure has an amyloid core covering residues 94-144. It comprises two protofilaments, each containing five beta-strands arranged as a long hairpin plus an N-terminal beta-strand. This N-terminal beta-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. (c) 2024 Elsevier Ltd. All rights reserved.

引用

页数：13