Folding & Design: introduction to a new journal.
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Biomedical subjects
FE Cohen
Publications and source records attributed to FE Cohen.
Scrapie prions: a three-dimensional model of an infectious fragment.
Backgound. A conformational change seems to represent the major difference between the scrapie prion protein (PrPSc) and its normal cellular isoform (PrPC). We recently proposed a set of four helix bundle models for the three-dimensional structure of PrPC that are consistent with a variety of spectroscopic and genetic data. Results. We report a plausible model for the three-dimensional structure of a biologically important fragment of PrPSc. The model of residues 108-218 was constructed by an approach that combines computational techniques and experimental data. The proposed structures of this fragment of PrPSc display a four-stranded beta-sheet covered on one face by two alpha-helices. Residues implicated in the prion species barrier are found to cluster on the solvent-accessible surface of the beta-sheet of one of the models. This interface could provide a structural template that would assist the conversion of PrPC to PrPSc and hence direct prion propagation. Conclusion. Molecular models of the PrP isoforms should prove very useful in developing structural hypotheses about the process by which PrPC is transformed into PrPSc, the mechanisms by which PrP gene mutations give rise to the inherited human prion diseases, and the species barrier that seems to protect humans from animal prions. It seems likely that PrPC represents a kinetically trapped intermediate in PrP folding.
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Adding backbone to protein folding: why proteins are polypeptides.
It is argued that the chemical nature of the polypeptide backbone is the central determinant of the three-dimensional structures of proteins. The requirement that buried polar groups form intramolecular hydrogen bonds limits the fold of the backbone to the well known units of secondary structure while the amino acid sequence chooses among the set of conformations available to the backbone. 'Sidechain-only' models, based for example on hydrophobicity patterns, fail to account for the properties of the backbone and thus will have difficulty capturing essential features of a folding pathway. This is evident from the incorrect predictions they make for the conformations of the limiting cases of all-hydrophobic or all-polar sequences.
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