Ubiquitin Interacting Motifs: Duality Between Structured and Disordered Motifs

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.

A context-dependent and disordered ubiquitin-binding motif

“…Ubiquitin-binding modules exist in many different proteins carrying out highly versatile tasks ranging from protein degradation to signal transduction and regulation [ 14 , 74 , 75 ]. For years, these modules have been seen as requiring a folded structure to interact with ubiquitin, either in the form of a small, folded domain or a single α-helix, but recent computational studies have suggested that some modules may retain some dynamics and disorder in the free state, allowing for folding-upon-binding to ubiquitin to canonical helical structures [ 35 ]. In the present work, we extend the spectrum of ubiquitin-binding modules to account for disordered extended structures in complex with ubiquitin.…”

“…Recent computational work addressing the properties of a subgroup of ubiquitin-binding domains has shown that a set of these can be disordered to some degree in their free state and fold into an α-helix in complex with ubiquitin, analogous with known UBD structures [ 35 ]. Additionally, in recent years, unconventional ubiquitin-binding regions in two unrelated IDPs: the deleted in split hand/split foot 1 (Dss1), a proteasome subunit [ 36 , 37 ] and the ubiquitin-conjugating enzyme E2 Cdc34 [ 38 ], have been reported.…”

Targeting the YXXΦ Motifs of the SARS Coronaviruses 1 and 2 ORF3a Peptides by In Silico Analysis to Predict Novel Virus—Host Interactions

“…Of course, the consensus pattern of the YXXΦ motif is not the absolute reason for functionality. Other factors, such as the presence of di-leucine residues, the surrounding amino acids or the presence of intrinsically disordered regions, as the ones identified near or between some of the putative YXXΦ motifs on ORF3a proteins ( Figure 3 b) have been proposed to influence the putative function of various motifs [ 97 ].…”

Structural insights into ATP-sensitive potassium channel mechanics: a role of intrinsically disordered regions

“…Most of well-known proteins still fold quite precisely, adopting their function-related structures. However, a significant proportion of proteins, or protein fragments, escape this rule and perform important tasks in the organism without exhibiting a defined secondary structure 1, 2…”

“…Most of well-known proteins still fold quite precisely, adopting their function-related structures. However, a significant proportion of proteins, or protein fragments, escape this rule and perform important tasks in the organism without exhibiting a defined secondary structure 1,2 Intrinsically disordered proteins (IDPs) or intrinsically disordered protein regions (IDRs) can adopt a whole ensemble of conformations and act while remaining unstructured. Analyses show that up to 67% of eukaryotic proteins contain at least one disordered region 1 .…”