Exam I Study Guide
Supplement
Prions, Protein Folding and Disease
Stanley B. Prusiner won the 1997 Nobel Prize in Physiology or Medicine for his work (and persistence!) on prions. This prize was exceptionally controversial, in part because his prion hypothesis seemingly violates Crick’s “Central Dogma” of molecular biology – information flows from DNA to protein in a unidirectional fashion.
- Why has the concept of Prions been so controversial?
- The Prion concept has been controversial in part because it posits that a disease state is transmitted to a new host without the use of nucleic acids. This is troubling to many because the prion diseases pathology occurs via the deposition of non-native protein “plaques” or precipitate deposits.
- The standard explanation for a deposit of an apparently “new” protein precipitate is that a pathogen has introduced a nucleic acid (DNA or RNA) coding for the new protein and it has hijacked the host protein biosynthetic apparatus to synthesize the protein.
- The other snag in the prion theory is that it has taken many years and many attempts to transmit prions or prion disease states in systems that can be convincingly demonstrated to NOT involve the transmission of nucleic acid.
- The prion diseases most closely resemble viruses. One way to conceive of viral infections is as an introduction of foreign (and disruptive) information into the host system (thus the use of the term "virus" for invasive information in computer systems). What "kind" of information does Prusiner postulate the prion transmits? How is this information transmitted/inherited?
- Prusiner postulates that prions DO NOT transmit heritable information such as is transmitted by DNA or RNA, rather they hijack host proteins that already exist (are coded by the host genome) by inducing them to change to an alternate, non-native, stable folded state.
- The folding information is tramsmitted by inducing a new folded state via surface-surface interaction with the foreign prion protein. The process may be envisioned as similar to epitaxial growth in crystals where a new substance may be induced to take on a non-native crystal form (lattice type) by growing on a foreign substrate—the new substance takes on the crystal form of the substrate.
- There seem to be genetically transmitted prion diseases (or predilections to prion diseases). How do these diseases fit within the Prusiner model?
- A genetic prediliction to prion diseases is explained by the host genome coding for a native protein that is has a less stable native folded state, and so it is more redily converted to the prion folded state. This is important as it allows the Prion Theory to not violate the basic tenant of the “Central Dogma” that only nucleic acids can transmit genetic information, an idea that has not been found to have any violations (we have yet to discover, after very extensive searching via experiment and theory, any way for proteins to transmit information for protein primary structure).
- Do you find Prusiner's arguments convincing? Those with a genetics background might help the rest of us in sorting out why most scientists would be much more comfortable with a DNA or RNA based infectious agent.
- Defend your opinion/thoughts.
- Discuss the prion disease mechanism in terms of protein folding (initial and final conformations, change of conformation, stability of conformations).
- The pre-prion protein appears to have a largely alpha-helical native structure favored in the normal folding process (kinetically favored, quasi-stable). The protein’s native conformation is induced to change into a more stable form that is largely folded into a beta sheet. It would seem that the beta “prion” folded form is not normally attained because the alpha form folds more rapidly, precluding the beta form under normal circumstances.
- Discuss rationales for the existence of prions. Why should we have them if they are so potentially damaging?
- Things that are potential but largely unrealized will not be excluded by evolutionary processes. Evolution selects for high reproductivity and works with what is already available—it does not get to “design” from scratch. Thus many of nature’s “designs” are wonderous but not optimal. If a protein has an advantageous function the fact that it may occasionally be subverted to harm its carrier will have little impact unless it frequently interferes with the host’s reproductive success. Keep in mind the example of Sickle cell anemia, a devastating genetic disease (lethal in homozygotes prior to reproduction without modern medical intervention) that is favored in parts of Africa because of its beneficial protection against malaria in single-copy carriers.
Last modified 24 February 2012