Conditional disorder in proteins: Functional transitions between order and disorder

Abstract

The classical view of protein function based on rigid, well-defined structures is being redefined by the emerging concept of intrinsic disorder. Conditionally disordered proteins (CDPs) represent a subset of cellular intrinsically disordered proteins (IDPs) that transition between ordered and disordered states in response to specific stimuli, such as redox changes, post-translational modifications, ligand binding, interaction with partners, or environmental stress. This review explores the diverse landscape of conditional disorder and encompasses cryptic or dormant disordered regions, redox-sensitive motifs, metamorphic proteins, and proteins exhibiting order-disorder-new order transitions. These dynamic transitions allow CDPs to perform specialized regulatory, signalling, and stress-responsive roles, which often act as interaction hubs in complex cellular networks. Importantly, conditional disorder is not an anomaly but a conserved and functionally relevant feature across many proteomes. We highlight mechanistic insights into disorder-to-order transitions and their implications for cellular plasticity, adaptability, and disease. We also discuss how the conformational heterogeneity of CDPs complicates structure-based drug design, while offering unique therapeutic opportunities. Future directions include the integration of advanced biophysical techniques, computational modelling, and profiling to map, characterize, and target CDPs with greater precision. Overall, understanding the molecular logics of the conditional disorder will open new frontiers in structural biology and offer a deeper appreciation of protein versatility beyond static structural paradigms.