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 language | English (US) |
|---|---|
| Pages (from-to) | 12955-12963 |
| Number of pages | 9 |
| Journal | Biochemistry |
| Volume | 43 |
| Issue number | 41 |
| DOIs | |
| State | Published - Oct 19 2004 |
| Externally published | Yes |
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- Biochemistry
Cite this
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 journal › Article
}
TY - JOUR
T1 - Preventing misfolding of the prion protein by trimethylamine N-oxide
AU - Bennion, Brian J.
AU - DeMarco, Mari L.
AU - Daggett, Valerie
PY - 2004/10/19
Y1 - 2004/10/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=5444232817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=5444232817&partnerID=8YFLogxK
U2 - 10.1021/bi0486379
DO - 10.1021/bi0486379
M3 - Article
C2 - 15476389
AN - SCOPUS:5444232817
VL - 43
SP - 12955
EP - 12963
JO - Biochemistry
JF - Biochemistry
SN - 0006-2960
IS - 41
ER -