Prions in Information Storage and Long Term Memory
From Icamipedia
Contents |
Introduction
Prion proteins are well known for the deadly diseases with which they are associated such as bovine spongiform encephalopathy, better known as “mad cow” disease, or Creutzfeldt-Jakob disease (CJD). However, the evil character given to this protein is starting to change as new research unveils the important roles these proteins may play. More and more findings are supporting the idea that prion proteins are involved in non-genetic information transfer between cells or organisms, by means of “self-perpetuating” protein conformational changes (1). The initial work that characterized these observations was carried out by Reed Wickner, a geneticist which worked with inheritable non-DNA elements in yeast (1). Inheritable non-DNA traits were first observed in fungi in the 1950's, and in yeast during the 1970's. The observation of non-genetic inheritance puzzled the scientific community for a long time as there were no known mechanisms for the process and also because it violated the standard ideas in genetics.
Self-perpetuation – How Yeasts Talk to Each Other
In 1994 Wickner proposed the idea of self-perpetuation of the yeast proteins [URE3] and [PSI+] in a report published in Science magazine. [URE3] (prion form of Ure2 protein) is a transcriptional repressor which induces the uptake of poor nitrogen sources in the presence of a good nitrogen source, and [PSI+] (prion form of Sup35 protein) affects translation termination by allowing some proteins to continue to be created while they would normally be terminated (1, 2). Wickner observed that Ure2 and Sup35 could spontaneously convert into their prion forms and once in these forms, they could convert other proteins around them into prions as well (3). The molecular interconversion could not only happen within each organism, but it could also take place in neighboring cells if [URE3] and [PSI+] were transferred among the cells. This was a crucial finding as it showed that the yeast cells could “transfer” information with each other without the need of genetic material. A few years later Wickner and colleagues showed that overexpressing Ure2 increased the spontaneous conversion to [URE3] and this interconversion was catalyzed by the prion-like domain of the protein (4).
The self-perpetuation model supported by these findings requires a molecule which can interconvert between two different structural states by either spontaneous or induced conversion, and once the molecule is in the converted prion state, it can induce the conversion of other normal proteins around it. The question arises to why does a prion protein induce other normal proteins to interconvert? The answer is that in order to maintain a permanent molecular change it must be immune to protein turnover. Prions, like any other proteins, are susceptible to degradation, so as the “older” prions are degraded, the newly synthesized proteins must be converted into the prion state to replace the degraded proteins.
Structure Determinants – How do we Know it's a Prion?
When Wickner labeled [URE3] and [PSI+] as prions, they were the only proteins other than [PrP] to be labeled as such. Since then, other proteins have been discovered which share common features and so they have been placed in the prion category. Some of these features are listed here:
- Contain an asparigine/glutamine rich domain (2)
- Contain intrinsically unstructured regions of 50 aminoacids or more (2)
- Contain oligopeptide repeats (2)
Some yeast prions also require the presence of chaperones.
Prions and Synapses – Making Long-term Molecular Memories
References
[1] Couzin, J. Molecular biology. in yeast, prions' killer image doesn't apply. Science (2002) 297: pp. 758-761.
[2] Shorter, J. & Lindquist, S. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet (2005) 6: pp. 435-450.
[3] Wickner, R.B. [ure3] as an altered ure2 protein: evidence for a prion analog in saccharomyces cerevisiae. Science (1994) 264: pp. 566-569.
[4] Masison, D.C., Maddelein, M.L. & Wickner, R.B. The prion model for [ure3] of yeast: spontaneous generation and requirements for propagation. Proc Natl Acad Sci U S A (1997) 94: pp. 12503-12508.
