Abstract
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.
Highlights
Protein biochemistry relied for a long time on the paradigm that a protein’s function is tied to its three-dimensional structure
In contrast with the results from WT-metaD, the REMD simulations tend to show a group of fully helical conformations of UIM3 (Supplementary Figure S2). These analyses suggest that the REMD simulations provide a limited sampling and they are still biased by the initial helical conformation of UIM3
We focused on the structural characterization of the conformational ensemble of a functional motif that has been classically defined for its helical conformation and originally associated with the binding of ubiquitin; the Ubiquitin Interacting Motif (UIM)
Summary
Protein biochemistry relied for a long time on the paradigm that a protein’s function is tied to its three-dimensional structure. Over the past 20 years, several proteins or regions in proteins that do not fit within the structure-function paradigm have been reported (Wright and Dyson, 1999; Chen and Kriwacki, 2018; Milles et al, 2018). They are known as intrinsically disordered proteins (IDPs) or regions (IDRs). Proteins containing IDRs constitute 30–44% of eukaryotic proteomes (Perdigão et al, 2015) They attain multiple and chameleon conformations for interactions with different partners (Wright and Dyson, 2014; Bugge et al, 2020).
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