Two different neurodegenerative diseases caused by proteins with similar structures
- Huaping Mo*,
- Richard C. Moore†,‡,
- Fred E. Cohen†,‡,§,
- David Westaway¶,
- Stanley B. Prusiner‡,‖,
- Peter E. Wright*,**, and
- H. Jane Dyson*,**
- *Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; †Institute for Neurodegenerative Diseases, ‖Department of Neurology, and §Departments of Pharmaceutical Chemistry, Cellular and Molecular Pharmacology, and Medicine, ‡Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143; and ¶Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 3H2, Canada
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Contributed by Stanley B. Prusiner
Abstract
The downstream prion-like protein (doppel, or Dpl) is a paralog of the cellular prion protein, PrPC. The two proteins have ≈25% sequence identity, but seem to have distinct physiologic roles. Unlike PrPC, Dpl does not support prion replication; instead, overexpression of Dpl in the brain seems to cause a completely different neurodegenerative disease. We report the solution structure of a fragment of recombinant mouse Dpl (residues 26–157) containing a globular domain with three helices and a small amount of β-structure. Overall, the topology of Dpl is very similar to that of PrPC. Significant differences include a marked kink in one of the helices in Dpl, and a different orientation of the two short β-strands. Although the two proteins most likely arose through duplication of a single ancestral gene, the relationship is now so distant that only the structures retain similarity; the functions have diversified along with the sequence.
Footnotes
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↵ ** To whom reprint requests should be addressed. E-mail: dyson{at}scripps.edu.
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Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID code 1I17).
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Data deposition: The NMR chemical shifts have been deposited in the BioMagResBank, www.bmrb.wisc.edu (accession no. 4938).
- Abbreviations:
- NOE,
- nuclear Overhauser effect;
- NOESY,
- NOE spectroscopy;
- HSQC,
- heteronuclear sequential quantum correlation
- Copyright © 2001, The National Academy of Sciences
