Preventing misfolding of the prion protein by trimethylamine N-oxide

Brian J. Bennion, Mari L. DeMarco, Valerie Daggett

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Transmissible spongiform encephalopathies are a class of fatal neurodegenerative diseases linked to the prion protein. The prion protein normally exists in a soluble, globular state (PrPC) that appears to participate in copper metabolism in the central nervous system and/or signal transduction. Infection or disease occurs when an alternatively folded form of the prion protein (PrPSc) converts soluble and predominantly α-helical PrPC into aggregates rich in β-structure. The structurally disordered N-terminus adopts β-structure upon conversion to PrPSc at low pH. Chemical chaperones, such as trimethylamine N-oxide (TMAO), can prevent formation of PrPSc in scrapie-infected mouse neuroblastoma cells [Tatzelt, J., et al. (1996) EMBO J. 15, 6363-6373]. To explore the mechanism of TMAO protection of PrPC at the atomic level, molecular dynamics simulations were performed under conditions normally leading to conversion (low pH) with and without 1 M TMAO. In PrPC simulations at low pH, the helix content drops and the N-terminus is brought into the small native β-sheet, yielding a PrPSc-like state. Addition of 1 M TMAO leads to a decreased radius of gyration, a greater number of protein-protein hydrogen bonds, and a greater number of tertiary contacts due to the N-terminus forming an Ω-loop and packing against the structured core of the protein, not due to an increase in the level of extended structure as with the PrPC to PrPSc simulation. In simulations beginning with the "PrPSc-like" structure (derived from PrPC simulated at low pH in pure water) in 1 M TMAO, similar structural reorganization at the N-terminus occurred, disrupting the extended sheet. The mechanism of protection by TMAO appears to be exclusionary in nature, consistent with previous theoretical and experimental studies. The TMAO-induced N-terminal conformational change prevents residues that are important in the conversion of PrPC to PrPSc from assuming extended sheet structure at low pH.

Original languageEnglish (US)
Pages (from-to)12955-12963
Number of pages9
JournalBiochemistry
Volume43
Issue number41
DOIs
StatePublished - Oct 19 2004
Externally publishedYes

Fingerprint

PrPSc Proteins
Neurodegenerative diseases
Scrapie
Signal transduction
Proteins
Prion Diseases
Neurology
Molecular Dynamics Simulation
trimethyloxamine
Prion Proteins
Prions
Neuroblastoma
Metabolism
Neurodegenerative Diseases
Molecular dynamics
Copper
Hydrogen
Signal Transduction
Hydrogen bonds
Theoretical Models

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bennion, B. J., DeMarco, M. L., & Daggett, V. (2004). Preventing misfolding of the prion protein by trimethylamine N-oxide. Biochemistry, 43(41), 12955-12963. https://doi.org/10.1021/bi0486379

Preventing misfolding of the prion protein by trimethylamine N-oxide. / Bennion, Brian J.; DeMarco, Mari L.; Daggett, Valerie.

In: Biochemistry, Vol. 43, No. 41, 19.10.2004, p. 12955-12963.

Research output: Contribution to journalArticle

Bennion, BJ, DeMarco, ML & Daggett, V 2004, 'Preventing misfolding of the prion protein by trimethylamine N-oxide', Biochemistry, vol. 43, no. 41, pp. 12955-12963. https://doi.org/10.1021/bi0486379
Bennion, Brian J. ; DeMarco, Mari L. ; Daggett, Valerie. / Preventing misfolding of the prion protein by trimethylamine N-oxide. In: Biochemistry. 2004 ; Vol. 43, No. 41. pp. 12955-12963.
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