Prion diseases are fatal transmissible neurodegenerative diseases that result from structural conversion of the prion protein into a disease-associated isoform. The prion protein contains a single disulfide bond. Our analysis of all NMR structures of the prion protein (total of 440 structures over nine species) containing an explicit disulfide bond reveals that the bond exists predominantly in a stable low-energy state, but can also adopt a high-energy configuration. The side chains of two tyrosine residues and one phenylalanine residue control access of solvent to the disulfide bond. Notably, the side chains rotate away from the disulfide bond in the high-energy state, exposing the disulfide bond to solvent. The importance of these aromatic residues for protein function was analysed by mutating them to alanine residues and analysing the properties of the mutant proteins using biophysical and cell biological approaches. Whereas the mutant protein behaved similarly to wild-type prion protein in recombinant systems, the mutants were retained in the endoplasmic reticulum of mammalian cells and degraded by the proteasomal system. The cellular behaviour of the aromatic residue mutants was similar to the cellular behaviour of a disulfide bond mutant prion protein in which the cysteine residues were replaced with alanine, a result which is consistent with an unstable disulfide bond in the aromatic residue mutants. These observations suggest that the conformation of the prion protein disulfide bond may have implications for correct maturation and function of this protein.
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Research Article|
May 13 2010
Changing the solvent accessibility of the prion protein disulfide bond markedly influences its trafficking and effect on cell function
Catherine A. Tabrett;
Catherine A. Tabrett
1
*Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
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Christopher F. Harrison;
Christopher F. Harrison
1
†Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville VIC 3010, Australia
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Bryan Schmidt;
Bryan Schmidt
*Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
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Shayne A. Bellingham;
Shayne A. Bellingham
†Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville VIC 3010, Australia
‡Mental Health Research Institute of Victoria, University of Melbourne, Parkville VIC 3010, Australia
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Tristan Hardy;
Tristan Hardy
*Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
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Yves-Henri Sanejouand;
Yves-Henri Sanejouand
§Laboratoire de Physique, Ecole Normale Superieure, 46 allees d'Italie, 69364 Lyon Cedex 07, France
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Andrew F. Hill;
†Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville VIC 3010, Australia
‡Mental Health Research Institute of Victoria, University of Melbourne, Parkville VIC 3010, Australia
2To whom correspondence should be addressed (email a.hill@unimelb.edu.au).
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Philip J. Hogg
Philip J. Hogg
*Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
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Publisher: Portland Press Ltd
Received:
October 21 2009
Revision Received:
March 08 2010
Accepted:
March 25 2010
Accepted Manuscript online:
March 25 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 428 (2): 169–182.
Article history
Received:
October 21 2009
Revision Received:
March 08 2010
Accepted:
March 25 2010
Accepted Manuscript online:
March 25 2010
Citation
Catherine A. Tabrett, Christopher F. Harrison, Bryan Schmidt, Shayne A. Bellingham, Tristan Hardy, Yves-Henri Sanejouand, Andrew F. Hill, Philip J. Hogg; Changing the solvent accessibility of the prion protein disulfide bond markedly influences its trafficking and effect on cell function. Biochem J 1 June 2010; 428 (2): 169–182. doi: https://doi.org/10.1042/BJ20091635
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