Genetic influence on the structural variations of the abnormal prion protein
- Piero Parchi*,†,
- Wenquan Zou*,
- Wen Wang*,
- Paul Brown‡,
- Sabina Capellari*,†,
- Bernardino Ghetti§,
- Nicolas Kopp¶,
- Walter J. Schulz-Schaeffer‖,
- Hans A. Kretzschmar‖,
- Mark W. Head**,
- James W. Ironside**,
- Pierluigi Gambetti*,‡‡, and
- Shu G. Chen*,‡‡
- *Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106; ‡Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892; §Department of Pathology, Indiana University Medical Center, Indianapolis, IN 46202; ¶Hôpital Neurologique Pierre Wertheimer, Lyon 69003, France; ‖Institut fur Neuropathologie, Georg-August-Universitat Göttingen, 37075 Göttingen, Germany; and **Creutzfeldt–Jakob Disease Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU, England
-
Communicated by D. Carleton Gajdusek, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France (received for review April 15, 2000)
Abstract
Prion diseases are characterized by the presence of the abnormal prion protein PrPSc, which is believed to be generated by the conversion of the α-helical structure that predominates in the normal PrP isoform into a β-sheet structure resistant to proteinase K (PK). In human prion diseases, two major types of PrPSc, type 1 and 2, can be distinguished based on the difference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites of PrPSc in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 PrPSc, respectively, and numerous secondary cleavages distributed along the region spanning residues 74–102. Accordingly, we identify three regions in PrPSc: one N-terminal (residues 23–73) that is invariably PK-sensitive, one C-terminal (residues 103–231) that is invariably PK-resistant, and a third variable region (residues 74–102) where the site of the PK cleavage, likely reflecting the extent of the β-sheet structure, varies mostly as a function of the PrP genotype at codon 129.
Footnotes
-
↵ † Present address: Department of Neurological Sciences, University of Bologna, Via Foscolo 7, 40123 Bologna, Italy.
-
↵ ‡‡ To whom reprint requests should be addressed. E-mail: sxc59{at}po.cwru.edu or pxg13{at}po.cwru.edu.
- Abbreviations:
- CJD,
- Creutzfeldt–Jakob disease;
- FFI,
- fatal familial insomnia;
- PK,
- proteinase K;
- PNGase F,
- peptide N-glycosidase F
- Copyright © 2000, The National Academy of Sciences
