Coding Regions of Intrinsic Disorder Accommodate Parallel Functions

Numerous DNA- and RNA-level functions are embedded in protein-coding regions, which constrains their structure, function, and evolution. Accumulating evidence suggests that such additional, overlapping functions occur preferentially in the coding sequences of intrinsically disordered proteins/regions (IDPs/IDRs), especially in those that are newly incorporated and thus have reduced selective pressure. It is the lack of strict structural constraints that makes disordered proteins more tolerant to mutations and thus more permissive to the appearance of overlapping functions within their coding sequences than structured domains. Therefore, IDPs/IDRs are often mosaics of segments fulfilling protein functionalities and intervening regions primarily carrying nucleotide-level functions. The ensuing complexification of gene-regulatory circuits may have contributed to the evolutionary spread of structural disorder in complex eukaryotic organisms.