Sequence-Based Fingerprinting of Intrinsically Disordered Regions

Abstract

Sequence conservation and the high fidelity of sequence-to-structure relationships enable the identification of protein sequence families. This is especially true of proteins that are capable of folding as autonomous units. However, over a third of the eukaryotic proteome consists of intrinsically disordered proteins and regions (IDRs) that either fold upon binding into distinct context-dependent structures or persist in disordered albeit functional states. Freed from the constraint of autonomous folding, the sequences of IDRs are frequently less well conserved as assessed by standard alignment-based metrics. Accordingly, traditional methods for sequence classification often fail when identifying sequence families that are defined by IDRs. The apparent lack of sequence conservation could be taken to mean that random sequences are interoperable with the sequences of IDRs, yet several recent studies show that this is clearly not the case. Biophysical studies have helped identify the existence of sequence-to-conformation relationships for IDPs. These relationships, in turn, govern the molecular functions of IDRs and by extrapolation we propose that there is an amino-acid based grammar that underlies sequence-to-function relationships as well. Sequence complexity, amino acid composition, and the linear patterning of different types of amino acids are among the main determinants of sequence-to-conformation relationships and the consequences for functions and phenotypes. We have used these sequence features as fingerprints to develop ways to delineate sequence families for IDRs. These measures are designed to enable the effective classification and comparison of IDRs, with applications towards sequence design, evolutionary analysis, and ultimately the prediction of molecular functions of IDRs. These efforts are likely to enable an improved understanding of the evolutionary determinants of IDRs versus intrinsically foldable regions.