Why do eukaryotic proteins contain more intrinsically disordered regions?

Abstract

Intrinsic disorder is much more abundant in eukaryotic than in prokaryotic proteins. However, the reason behind this is unclear. It has been proposed that the disordered regions are functionally important for regulation in eukaryotes, but it has also been proposed that the difference is a result of lower selective pressure in eukaryotes. Almost all studies intrinsic disorder is predicted from the amino acid sequence of a protein. Therefore, there should exist an underlying difference in the amino acid distributions between eukaryotic and prokaryotic proteins causing the predicted difference in intrinsic disorder. To obtain a better understanding of why eukaryotic proteins contain more intrinsically disordered regions we compare proteins from complete eukaryotic and prokaryotic proteomes.Here, we show that the difference in intrinsic disorder origin from differences in the linker regions. Eukaryotic proteins have more extended linker regions and, in particular, the eukaryotic linker regions are more disordered. The average eukaryotic protein is about 500 residues long; it contains 250 residues in linker regions, of which 80 are disordered. In comparison, prokaryotic proteins are about 350 residues long and only have 100-110 residues in linker regions, and less than 10 of these are intrinsically disordered.Further, we show that there is no systematic increase in the frequency of disorder-promoting residues in eukaryotic linker regions. Instead, the difference in frequency of only three amino acids seems to lie behind the difference. The most significant difference is that eukaryotic linkers contain about 9% serine, while prokaryotic linkers have roughly 6.5%. Eukaryotic linkers also contain about 2% more proline and 2-3% fewer isoleucine residues. The reason why primarily these amino acids vary in frequency is not apparent, but it cannot be excluded that the difference is serine is related to the increased need for regulation through phosphorylation and that the proline difference is related to increase of eukaryotic specific repeats.1/30 domains [11]. With a larger fraction of multi-domain proteins, it follows that eukaryotic proteins should have more linker regions -connecting the domains. Linker regions vary substantially in lengths and are often intrinsically disordered [12].The increased number of repeats appears to be a feature of multicellular organisms [8]. Repeat proteins are common in signaling and are associated with some cancers. These repeats have been proposed to provide the eukaryotes with an extra source of variability to compensate for low generation rates [13].The origin of the increase in intrinsically disordered regions in eukaryotic proteins is less well understood. Intrinsic disorder is frequent in all eukaryotic phyla, and even among viral proteins [14]. There is a spectrum of different types of disorder, spanning from increased flexibility to completely disordered proteins. Intrinsically disordered proteins exist among many classes of proteins with different functions, but the difference bet...

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