Ubiquitin is a small protein at the heart of many cellular processes, and several different protein domains are known to recognize and bind ubiquitin. A common motif for interaction with ubiquitin is the Ubiquitin Interacting Motif (UIM), characterized by a conserved sequence signature and often found in multi-domain proteins. Multi-domain proteins with intrinsically disordered regions mediate interactions with multiple partners, orchestrating diverse pathways. Short linear motifs for binding are often embedded in these disordered regions and play crucial roles in modulating protein function. In this work, we investigated the structural propensities of UIMs using molecular dynamics simulations and NMR chemical shifts. Despite the structural portrait depicted by X-crystallography of stable helical structures, we show that UIMs feature both helical and intrinsically disordered conformations. Our results shed light on a new class of disordered UIMs. This group is here exemplified by the C-terminal domain of one isoform of ataxin-3 and a group of ubiquitin-specific proteases. Intriguingly, UIMs not only bind ubiquitin. They can be a recruitment point for other interactors, such as parkin and the heat shock protein Hsc70-4. Disordered UIMs can provide versatility and new functions to the client proteins, opening new directions for research on their interactome.
Bibliographical noteFunding Information:
EP group was supported by Carlsberg fondet Distinguished Fellowship (CF18-0314), Danmarks Grundforskningsfond (DNRF125) and NovoNordisk Fonden Bioscience and Basic Biomedicine NNF20OC0065262. BA was supported by COST-STSM-BM1405-34558. GI was supported by a Marie Curie IEF Fellowship. BK was supported by Novo Nordisk Foundation Challenge grant REPIN – rethinking protein interactions. GS was supported by Canadian Institutes of Health Research (PJT – 166019). The calculations described in this paper were performed using the ISCRA-CINECA grant diso-UIMs HP10C4LACQ.
- Intrinsic disorder
- Molecular dynamics
- Moonlight functions
- Peptide arrays
- Short linear motifs