A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions

Abstract

Glutamine/asparagine (Q/N)-rich domains have a high propensity to form self-propagating amyloid fibrils. This phenomenon underlies both prion-based inheritance in yeast and aggregation of a number of proteins involved in human neurodegenerative diseases. To examine the prevalence of this phenomenon, complete proteomic sequences of 31 organisms and several incomplete proteomic sequences were examined for Q/N-rich regions. We found that Q/N-rich regions are essentially absent from the thermophilic bacterial and archaeal proteomes. Moreover, the average Q/N content of the proteins in these organisms is markedly lower than in mesophilic bacteria and eukaryotes. Mesophilic bacterial proteomes contain a small number (0-4) of proteins with Q/N-rich regions. Remarkably, Q/N-rich domains are found in a much larger number of eukaryotic proteins (107-472 per proteome) with diverse biochemical functions. Analyses of these regions argue they have been evolutionarily selected perhaps as modular "polar zipper" protein-protein interaction domains. These data also provide a large pool of potential novel prion-forming proteins, two of which have recently been shown to behave as prions in yeast, thus suggesting that aggregation or prion-like regulation of protein function may be a normal regulatory process for many eukaryotic proteins with a wide variety of functions.

Figure 1

Many eukaryotic proteins contain Q/N-rich regions. The percent of ORFs with a region of 80 consecutive amino acids containing a Q/N content of at least 30 was determined for the indicated proteomes.

Figure 2

Expected and observed distributions of Q/N content of the best 80 mers across mesophilic and thermophilic proteomes. A comparison of the expected and observed distributions of Q/N contents across the most Q/N-rich regions of (a) eukaryotes, (b) mesophilic bacteria, (c) thermophilic bacteria, and (d) archaea. Arrows indicate the minimum Q/N content required for a domain to be considered Q/N rich. (a Inset) Magnification of the observed and expected distributions of Q/N-rich regions. Expected values were calculated on the basis of the average Q/N content per best 80 mer for each of the four types of organisms.

Figure 3

Thermophiles have a lower Q/N content and higher glutamate and valine content than mesophiles. The average percent amino acid content per ORF per proteome was determined for the completed proteomes. Shown are glutamine (Q), asparagine (N), glutamate (E), and valine (V). The other amino acids showed little variation. Error bars indicate the observed variance among the indicated class.