Prion protein remains the only known example of a protein capable of propagating a self-replicating conformation that can spread a disease (transmissible spongiform encephalopathy) across individuals and is thereby fitting of its name as an “infectious protein.”16,17
However, additional proteins exhibiting prion-like behavior are also observed in yeast, invertebrate and mammalian cells. In these cases the adoption of an alternate protein conformation and template based spreading of this conformation to the normal form, appears not to be deleterious and cause disease, but instead regulates the function of the aggregating protein.
Prion-like behavior of proteins is best characterized in yeast.18,19
The Sup35 protein is normally required for translational termination; however, under certain (particularly stressful) conditions it can form a self-propagating amyloid conformation transmissible to offspring, which is dependent on an intrinsically disordered region at the N-terminus particularly rich in glutamine (Q) and asparagine (N) residues.20
Because this Q/N rich region is required for prion like propagation, it is referred to as the “prion domain.” Evidence supports that under stressful environmental conditions, induction of the Sup35 prion state leads to loss of Sup35 function and widespread read through of stop codons, allowing the rapid emergence of novel phenotypes.21
Therefore, rather than representing a disease, prion domain mediated aggregation of Sup35 may actually be an adaptive strategy to provide immediate phenotypic diversity under stressful conditions.19
The prion-domains of most yeast prions are similarly Q/N rich, including those in Ure2 and Rnq1, although others (including HET-s) are not. Therefore, while Q/N rich domains are permissive to allow a protein to adopt a prion-like conformational state, they are not absolutely required. A growing body of work has supported that while not all Q/N domain containing yeast proteins can function as prions, they share a strong tendency to self-aggregate when overexpressed.22,23
There is also evidence for prion like behavior of a Q/N rich protein in Aplysia.24
CPEB is a RNA binding protein involved in regulating local synaptic protein synthesis. Synaptic activity appears to shift apCPEB from a monomeric to a multimeric form, which is dependent on the Q/N rich domain. In the multimeric form, apCPEB is active and regulates local mRNA translation to maintain synaptic facilitation. Similar behavior has also been observed in Drosophila where the prion-related Q/N domain of Pumilio, another RNA binding protein, regulates self-aggregation and post-synaptic translational suppression.25
Finally, the mammalian genome contains a large number of proteins with Q/N rich prion related domains that may similarly use self-aggregation to modulate their activity.26
A well studied example is the RNA-binding protein TIA-1, which is a key component of stress granules, cytoplasmic RNA-protein complexes formed under conditions of cellular stress which mediate mRNA translational suppression.27
The prion related domain of TIA-1 is necessary for it to aggregate and organize stress granule formation.28
A similar mechanism using Q/N domain mediated aggregation of RNA binding proteins also appears to be involved in the formation of P-bodies.29
Therefore, a consistent theme for proteins containing prion-related Q/N rich domains from yeast through mammals is one of stimulus induced conformational change leading to self aggregation (often from environmental stress), which then alters protein function to organize an adaptive response (form stress granules, alter synaptic translation, etc.).