Sequence- and chemical specificity define the functional landscape of intrinsically disordered regions

Abstract

Abstract Intrinsically disordered protein regions (IDRs) pervasively engage in essential molecular functions, yet they are often poorly conserved as assessed by sequence alignment. To understand the seeming paradox of how sequence variability is compatible with persistent function, we examined the functional determinants for a poorly conserved but essential IDR. We show that IDR function depends on two distinct but related properties: sequence- and chemical specificity. While sequence-specificity works via linear binding motifs, chemical specificity reflects the sequence-encoded chemistry of multivalent interactions through amino acids across an IDR. Unexpectedly, a binding motif that is essential in the wild-type IDR can be removed if compensatory changes to the sequence chemistry are made, highlighting the orthogonality and interoperability of both properties and providing a much deeper sequence space compatible with function. Our results provide a general framework to understand the functional constraints on IDR sequence evolution.