Intrinsically disordered proteins (IDPs) play central roles in cellular signaling and regulation by mediating dynamic, context-dependent protein-protein interactions. While IDPs exist as conformational ensembles in their unbound state, they often undergo folding transitions to form structured complexes upon partner protein binding. This process is often thought to involve short linear motifs that fold in a largely cooperative, single step, however, growing evidence suggests that IDPs may follow more complex, multistep pathways involving partially structured intermediates.
Researchers at the IBS (SIGNAL and EPIGEN groups), in collaboration with teams at the IAB in Grenoble (Palencia) and the ENS in Paris (Bouvignies), investigated the interaction between the intrinsically disordered scaffold protein POSH and the small GTPase Rac1, an interaction which triggers apoptosis via the JNK signaling pathway. Using NMR spectroscopy and X-ray crystallography, they showed that POSH transitions from a disordered ensemble to an ordered bound state through sequential folding events. Initial partial engagement via a CRIB motif anchors the complex and promotes folding of a first recognition element (MRE1), which in turn enables folding of a second element (MRE2). Each step depends on the successful structuring of the preceding one, revealing a hierarchical folding-upon-binding mechanism. These results highlight folding intermediates and conformational transitions as promising targets for therapeutic intervention in IDPs.
Hierarchical Folding-Upon-Binding of an Intrinsically Disordered Protein. LF Kjaer, FS Ielasi, T Winbolt, E Delaforge , M Tengo, LM Bessa, L Mariño Pérez, E Boeri Erba, G Bouvignies*, A Palencia*, MR Jensen*. Nature Commun. (2025), 16, 11346. https://doi.org/10.1038/s41467-025-66420-5
Contact : Malene R. Jensen (IBS/Structural Dynamics of Signalling Complexes Group)