Why do eukaryotic proteins contain more intrinsically disordered regions?

Abstract

Intrinsic disorder is more abundant in eukaryotic than prokaryotic proteins. Methods predicting intrinsic disorder are based on the amino acid sequence of a protein. Therefore, there must exist an underlying difference in the sequences between eukaryotic and prokaryotic proteins causing the (predicted) difference in intrinsic disorder. By comparing proteins, from complete eukaryotic and prokaryotic proteomes, we show that the difference in intrinsic disorder emerges from the linker regions connecting Pfam domains. Eukaryotic proteins have more extended linker regions, and in addition, the eukaryotic linkers are significantly more disordered, 38% vs. 12-16% disordered residues. Next, we examined the underlying reason for the increase in disorder in eukaryotic linkers, and we found that the changes in abundance of only three amino acids cause the increase. Eukaryotic proteins contain 8.6% serine; while prokaryotic proteins have 6.5%, eukaryotic proteins also contain 5.4% proline and 5.3% isoleucine compared with 4.0% proline and ≈ 7.5% isoleucine in the prokaryotes. All these three differences contribute to the increased disorder in eukaryotic proteins. It is tempting to speculate that the increase in serine frequencies in eukaryotes is related to regulation by kinases, but direct evidence for this is lacking. The differences are observed in all phyla, protein families, structural regions and type of protein but are most pronounced in disordered and linker regions. The observation that differences in the abundance of three amino acids cause the difference in disorder between eukaryotic and prokaryotic proteins raises the question: Are amino acid frequencies different in eukaryotic linkers because the linkers are more disordered or do the differences cause the increased disorder?

The protein domains of vertebrate species in which selection is more effective have greater intrinsic structural disorder

“…High ISD is also favored during the gene birth process (McLysaght and Hurst 2016; Wilson et al 2017; Foy et al 2019; James et al 2020; Kosinski et al 2020). Our results showing a preference for high ISD are surprising given that prokaryotes are more exquisitely adapted than eukaryotes at the molecular level (Liberles et al 2012; Ahrens et al 2017), yet have lower ISD (Ahrens et al 2017; Basile et al 2019). The obvious reason for the apparent discrepancy is that prokaryotes and eukaryotes contain different protein-coding sequences.…”

“…As an example of the use of CAIS, we go on to investigate protein intrinsic structural disorder (ISD). ISD is more abundant in eukaryotic than prokaryotic proteins (Ahrens et al 2017; Basile et al 2019), suggesting that low ISD might be favored by more effective selection (Liberles et al 2012; Ahrens et al 2017). This difference in structural disorder between eukaryotes and prokaryotes is strongest in the regions between annotated domains, both in abundance and degree of disorder, but the same difference is also visible in protein domains (Basile et al 2019).…”

A New Census of Protein Tandem Repeats and Their Relationship with Intrinsic Disorder

“…Intrinsic disorder has been found in different regions of proteins with different structures, enabling an array of functions like recognition domains, folding inhibitors, flexible linkers, etc. [27,28]. Both TR and intrinsic disordered regions (IDR) tend to be over-represented in the hubs of protein-protein interaction networks [29,30].…”

Flexibility and intrinsic disorder are conserved features of hepatitis C virus E2 glycoprotein

“…Intrinsically disordered protein regions (IDPR) are important for the function and regulation of a wide variety of proteins, particularly in eukaryotes [45][46][47][48]. Given the high flexibility of the variable regions we asked whether E2 contains any putative IDPR.…”