The Val-210-Ile pathogenic Creutzfeldt-Jakob disease mutation increases both the helical and aggregation propensities of a sequence corresponding to helix-3 of PrP(C)

Thompson, Andrew J., Barnham, Kevin J., Norton, Raymond S. and Barrow, Colin J. 2001, The Val-210-Ile pathogenic Creutzfeldt-Jakob disease mutation increases both the helical and aggregation propensities of a sequence corresponding to helix-3 of PrP(C), Biochimica et biophysical acta (BBA) - protein structure and molecular enzymology, vol. 1544, no. 1-2, pp. 242-254, doi: 10.1016/S0167-4838(00)00225-9.

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Title The Val-210-Ile pathogenic Creutzfeldt-Jakob disease mutation increases both the helical and aggregation propensities of a sequence corresponding to helix-3 of PrP(C)
Author(s) Thompson, Andrew J.
Barnham, Kevin J.
Norton, Raymond S.
Barrow, Colin J.ORCID iD for Barrow, Colin J. orcid.org/0000-0002-2153-7267
Journal name Biochimica et biophysical acta (BBA) - protein structure and molecular enzymology
Volume number 1544
Issue number 1-2
Start page 242
End page 254
Total pages 13
Publisher Elsevier
Place of publication Amsterdam, The Netherlands
Publication date 2001-01-12
ISSN 0006-3002
Keyword(s) Amino Acid Sequence
Circular Dichroism
Creutzfeldt-Jakob Syndrome
Isoleucine
Molecular Sequence Data
Mutation
Nuclear Magnetic Resonance, Biomolecular
PrPC Proteins
Protein Structure, Secondary
Valine
aggregation
prion
conformation
pathogenic mutation
Summary A peptide corresponding to the third helical region within the PrP(C) protein, from residues 198 to 218 (helix-3), was synthesised with and without the familial 210-Val to Ile Creutzfeldt-Jakob disease mutation. The NMR structure of PrP(C) predicts no global variation in stability for this mutation, indicating that local sequence rather than global structural factors are involved in the pathological effects of this mutation. 1H NMR analysis of peptides with and without this mutation indicated that it had no significant effect on local helical structure. Temperature denaturation studies monitored by CD showed that the mutation increased the helical content within this region (helical propensity), but did not stabilise the helix toward denaturation (helical stability). Aggregation data indicated that, in addition to increasing helical propensity, this mutation increased the aggregation propensity of this sequence. CD and NMR data indicate that helical interactions, stabilised by the Val-210-Ile mutation, may precede the formation of beta-sheet aggregates in this peptide sequence. Therefore, this pathological mutation probably does not facilitate PrP(C) to PrP(Sc) conversion by directly destabilising the helical structure of PrP(C), but may preferentially stabilise PrP(Sc) by facilitating beta-sheet formation within this sequence region of PrP. In addition, helical interactions between helix-3 in two or more PrP(C) molecules may promote conversion to PrP(Sc).
Language eng
DOI 10.1016/S0167-4838(00)00225-9
Field of Research 06 Biological Sciences
02 Physical Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2001, Elsevier Science
Persistent URL http://hdl.handle.net/10536/DRO/DU:30099783

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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