CIDER: Classification of Intrinsically Disordered Ensemble Regions

Abstract

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins fail to fold into well-defined three-dimensional structures as autonomous units. These sequences play important functional roles in signaling pathways, transcriptional regulation, and RNA metabolism. Recent studies have uncovered the physical principles underlying the relationships between IDP / IDR sequences and the range of conformations they adopt. IDP / IDR sequences can be classified into distinct conformational classes based on their amino acid compositions. These classes reflect the sequence-encoded balance between solvent-mediated intrachain electrostatic repulsions and attractions. Specifically, the number and linear sequence distribution of oppositely charged residues partitions the space of IDP / IDR sequences into globules, chimeras of globules and coils, designable random coils, and semi-flexible rod-like conformations.Here, we present CIDER (Classification of Intrinsically Disordered Ensemble Regions) [http://pappulab.wustl.edu/CIDER]. The CIDER webserver provides a rapid and intuitive computational route for designating the appropriate conformational class to a sequence and calculating a number of key parameters that enable inferences regarding conformational properties of IDPs / IDRs. CIDER is freely available and can be used online via a web server to achieve rapid annotation of sequence-disorder relationships for IDPs / IDRs. We also present a freely available non-web version (localCIDER), which we use to perform a high throughput proteomic level sequence analysis to uncover patterns that govern known phosphorylation sites within IDP sequences. The correlation between known phosphosites and the distribution and fraction of charged residues suggests that phosphorylation is used to modulate the underlying charge patterning to engender an expansion of the disordered sequence. This hints at the use of phosphorylation as a reversible switch to toggle IDPs between distinct conformation al classes.