» Articles » PMID: 12556465

Determinants of the in Vivo Folding of the Prion Protein. A Bipartite Function of Helix 1 in Folding and Aggregation

Overview
Journal J Biol Chem
Specialty Biochemistry
Date 2003 Jan 31
PMID 12556465
Citations 32
Authors
Affiliations
Soon will be listed here.
Abstract

Misfolding of the mammalian prion protein (PrP) is implicated in the pathogenesis of prion diseases. We analyzed wild type PrP in comparison with different PrP mutants and identified determinants of the in vivo folding pathway of PrP. The complete N terminus of PrP including the putative transmembrane domain and the first beta-strand could be deleted without interfering with PrP maturation. Helix 1, however, turned out to be a major determinant of PrP folding. Disruption of helix 1 prevented attachment of the glycosylphosphatidylinositol (GPI) anchor and the formation of complex N-linked glycans; instead, a high mannose PrP glycoform was secreted into the cell culture supernatant. In the absence of a C-terminal membrane anchor, however, helix 1 induced the formation of unglycosylated and partially protease-resistant PrP aggregates. Moreover, we could show that the C-terminal GPI anchor signal sequence, independent of its role in GPI anchor attachment, mediates core glycosylation of nascent PrP. Interestingly, conversion of high mannose glycans to complex type glycans only occurred when PrP was membrane-anchored. Our study indicates a bipartite function of helix 1 in the maturation and aggregation of PrP and emphasizes a critical role of a membrane anchor in the formation of complex glycosylated PrP.

Citing Articles

Topological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases.

Gogte K, Mamashli F, Herrera M, Kriegler S, Bader V, Kamps J Proc Natl Acad Sci U S A. 2024; 122(1):e2415250121.

PMID: 39739794 PMC: 11725851. DOI: 10.1073/pnas.2415250121.


VCP/p97 mediates nuclear targeting of non-ER-imported prion protein to maintain proteostasis.

Banik P, Ray K, Kamps J, Chen Q, Luesch H, Winklhofer K Life Sci Alliance. 2024; 7(6).

PMID: 38570188 PMC: 10992997. DOI: 10.26508/lsa.202302456.


Methionine oxidation within the prion protein.

Bettinger J, Ghaemmaghami S Prion. 2020; 14(1):193-205.

PMID: 32744136 PMC: 7518762. DOI: 10.1080/19336896.2020.1796898.


Disulfide-crosslink scanning reveals prion-induced conformational changes and prion strain-specific structures of the pathological prion protein PrP.

Taguchi Y, Lu L, Marrero-Winkens C, Otaki H, Nishida N, Schatzl H J Biol Chem. 2018; 293(33):12730-12740.

PMID: 29934306 PMC: 6102138. DOI: 10.1074/jbc.RA117.001633.


The Sec61/SecY complex is inherently deficient in translocating intrinsically disordered proteins.

Gonsberg A, Jung S, Ulbrich S, Origi A, Ziska A, Baier M J Biol Chem. 2017; 292(52):21383-21396.

PMID: 29084847 PMC: 5766967. DOI: 10.1074/jbc.M117.788067.