Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure |
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Authors: | William Wan Jan St?hr Amy Kendall Gerald Stubbs |
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Affiliation: | 1.Department of Biological Sciences and Center for Structural Biology; Vanderbilt University; Nashville, TN USA;;2.Institute for Neurodegenerative Diseases and Department of Neurology; University of California, San Francisco; San Francisco, CA USA |
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Abstract: | Self-propagation of aberrant protein folds is the defining characteristic of prions. Knowing the structural basis of self-propagation is essential to understanding prions and their related diseases. Prion rods are amyloid fibrils, but not all amyloids are prions. Prions have been remarkably intractable to structural studies, so many investigators have preferred to work with peptide fragments, particularly in the case of the mammalian prion protein PrP. We compared the structures of a number of fragments of PrP by X-ray fiber diffraction, and found that although all of the peptides adopted amyloid conformations, only the larger fragments adopted conformations that modeled the complexity of self-propagating prions, and even these fragments did not always adopt the PrP structure. It appears that the relatively complex structure of the prion form of PrP is not accessible to short model peptides, and that self-propagation may be tied to a level of structural complexity unobtainable in simple model systems. The larger fragments of PrP, however, are useful to illustrate the phenomenon of deformed templating (heterogeneous seeding), which has important biological consequences. |
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Keywords: | prion structure peptide models self-propagation amyloid fiber diffraction protein aggregation |
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