Selection maintains signaling function of a highly diverged intrinsically disordered region

Abstract

Intrinsically disordered regions (IDRs) are characterized by their lack of stable secondary or tertiary structure and comprise a large part of the eukaryotic proteome. Although these regions play a variety of signaling and regulatory roles, they appear to be rapidly evolving at the primary sequence level. To understand the functional implications of this rapid evolution, we focused on a highly diverged IDR in Saccharomyces cerevisiae that is involved in regulating multiple conserved MAPK pathways. We hypothesized that under stabilizing selection, the functional output of orthologous IDRs could be maintained, such that diverse genotypes could lead to similar function and fitness. Consistent with the stabilizing selection hypothesis, we find that diverged, orthologous IDRs can mostly recapitulate wildtype function and fitness in S. cerevisiae. We also find that the electrostatic charge of the IDR is correlated with signaling output and, using phylogenetic comparative methods, find evidence for selection maintaining this quantitative molecular trait despite underlying genotypic divergence.C urrent predictions suggest that close to 40% of all proteins in eukaryotic organisms are either entirely disordered or contain sizeable regions that are disordered, meaning they do not autonomously fold into defined secondary or tertiary structures (1, 2). These intrinsically disordered regions (IDRs) are thought to have important implications for protein function (3, 4) and are known to play regulatory roles, often through short linear motifs (SLiMs) that control protein-protein interactions, localization, degradation, and posttranslational modifications (5, 6). Although proteome-wide studies have provided in silico evidence for conservation of length (7) and composition (8) in some IDRs, reports of increased rates of insertions and deletions (9-13) and amino acid substitutions (14) in IDRs are indicative of their rapid evolution compared with ordered regions. In addition, although some SLiMs are indeed conserved in IDRs (15-17), others appear in clusters where precise position and number are not conserved (18)(19)(20). Although it is reasonable to assume that conservation of sequence in IDRs is indicative of functional conservation of SLiMs, it is more difficult to interpret the functional consequences of IDRs that are highly diverged at the sequence level: These may represent either nonfunctional sequences evolving in the absence of constraint or weakly constrained functional elements that are gained or lost in a compensatory manner [undergoing evolutionary turnover (as described in refs. 18, 21)], such that they are not conserved at the amino acid sequence level.Like IDRs, noncoding DNA often shows relatively rapid evolution and weak constraints at the sequence level (22). Interestingly, IDRs show other parallels with noncoding DNA (18,23,24). For example, nonconserved clusters of phosphorylation sites in IDRs are reminiscent of nonconserved transcription factor binding sites in enhancers. Although these enhancers and the bi...

A non-canonical histone acetyltransferase targets intragenic enhancers and regulates plant architecture

“…6d). These findings support the hypothesis that such homologous IDRs retain similar functions, despite extensive sequence divergence 45 .…”

“…6b and 4h). As IDRs are generally evolving rapidly, at the primary sequence level, it is currently difficult to predict whether their functional consequences are preserved during the evolution of CYC/TB1-like proteins 45 .…”

Evolutionary forces on different flavors of intrinsic disorder in the human proteome

“…At the same time, we speculate that IDPs have a high tolerance to mutations (both neutral and adaptive) but also a selective propensity to preserve their structural disorder, i.e., flexibility and conformational dynamics under physiological conditions. In support of that, different experimental and computational analyses showed that function and dynamic behavior of intrinsically disordered proteins are under selection and they are conserved in the face of negligible sequence conservation (Daughdrill et al, 2007;Lemas et al, 2016;Zarin et al, 2017;Walter et al, 2019). Additionally, there could be a strong selection to reduce the adverse effects of large concentrations of IDPs by tightly controlling their expression at all levels of transcription, translation, and protein degradation (Gsponer et al, 2008).…”

Integrating multiple experimental data to determine conformational ensembles of an intrinsically disordered protein

“…Given the importance of specific amino-acid motifs, sequence composition, and sequence patterning [13][14][15][16], it is not obvious that statistical laws derived for homopolymers in the limit of infinitely long chains will always satisfactorily describe finite-length heteropolymeric IDPs. This conformational diversity will likely not be captured by a single mean-field descriptor of polymer behaviour, such as a scaling exponent ν, or a single global dimension, such as the radius of gyration R g .…”