Identifying molecular features that are associated with biological function of intrinsically disordered protein regions

Previously, we showed that intrinsically disordered regions in proteins (IDRs) contain multiple sequence-distributed molecular features that are conserved over evolution, despite little sequence similarity that can be detected in alignments (Zarin et al. 2019). Here, we aim to use these molecular features to make specific functional predictions for individual IDRs and identify the molecular features within them that are responsible for specific functions. We find that the predictable functions are diverse, identifying previously known associated molecular features, as well as features that were previously not known to be associated with these functions. We experimentally confirm that elevated isoelectric point and hydrophobicity, features that are positively associated with mitochondrial localization, are necessary for mitochondrial targeting function. Remarkably, increasing isoelectric point in a synthetic IDR restores weak mitochondrial targeting. We believe feature analysis represents a new systematic approach to understand how biological functions of IDRs are specified by their protein sequences.