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Facilitator Questions
How might stress influence prion formation and inheritance? Prions may accelerate evolution. Is it possible for organisms to evolve mechanisms for evolvability? Kirschner M and Gerhart J. (1998) Evolvability. Proc. Natl. Acad. Sci. 95, 8420-8427
From a structural standpoint, consider the different steps that are involved with prion replication – association, conformational conversion, and fiber division. A) How do the non-prion conformer and the prion conformer recognize and associate with one another? What are the attractive forces? B) What are the characteristics of the non-prion conformer that allow templating to happen? What causes specificity? C) What variable property of the amyloid fibers themselves might be important for prion propagation?
Aggregation generally inhibits protein activity. This can be a direct consequence of proteins failing to access their native, active conformations. Evidence for the mammalian prion protein, PrP, suggests that much of the protein undergoes extensive conformation rearrangements in the prion state. However, other known prions are modular and have a distinct region of the protein that is involved with aggregation, and another (non-prion) region that generally retains its native fold and activity. Why then do prions often cause loss-of-function phenotypes?
There are also examples of gain-of-function prions. How might prions cause increased protein activity? |
