Proteome-wide signatures of function in highly diverged intrinsically disordered regions

Abstract

Intrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as "evolutionary signatures" of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue function in vivo, and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.

Entropy and Information within Intrinsically Disordered Protein Regions

“…Proteins that lack stable tertiary structure in their native form, known as intrinsically disordered proteins and regions (IDRs), comprise a large fraction of the eukaryotic proteome [ 6 , 7 ]. Many studies indicate that IDRs often exhibit large evolutionary sequence variation [ 8 , 9 , 10 ] and sample a vast 3D conformational space [ 11 ]. However, the apparent randomness of IDR evolution and 3D conformations is at odds with the diversity and significance of IDRs’ biological roles in regulatory [ 8 , 12 , 13 ] and signaling processes [ 14 , 15 ], and their frequent implications in disease [ 14 , 16 , 17 , 18 ].…”

“…Nonetheless, there is increasing appreciation of the critical biological function of disordered regions with little positional information [ 9 , 10 ]. How can we reconcile this contradiction?…”

“…This suggests that IDR sequences do contain some form of information, but that it is not detectible using sequence alignment-based techniques, which assume that each position carries information independently. Recently, we and others have begun to detect evolutionary signatures in disordered regions that are largely devoid of positional information [ 9 , 10 , 59 , 60 ]. This revealed that most of the apparently highly diverged IDRs in the yeast proteome contain multiple conserved molecular features in the form of physicochemical properties (e.g., net charge, isoelectric point, hydrophobicity, fraction of polar residues, etc.…”

“…), amino acid repeats (e.g., RG, RGG, QQ), sequence complexity, and sequence motifs (e.g., phosphorylation motifs, proline-rich motifs, nuclear localization signals, mitochondrial localization motifs, etc.) [ 10 ]. The evolutionary signatures in IDRs establish how natural selection can preserve distinct molecular features predictive of function, and suggest that, in addition to sequence motifs, bulk properties of disordered regions encode functional information stored in IDRs [ 10 ].…”

“…[ 10 ]. The evolutionary signatures in IDRs establish how natural selection can preserve distinct molecular features predictive of function, and suggest that, in addition to sequence motifs, bulk properties of disordered regions encode functional information stored in IDRs [ 10 ].…”