Table5_Ubiquitin Interacting Motifs: Duality Between Structured and Disordered Motifs.pdf

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.

泛素（Ubiquitin）是一类小分子蛋白质，是众多细胞过程的核心。目前已知有多种不同的蛋白质结构域可识别并结合泛素，其中与泛素相互作用的常见基序为泛素相互作用基序（Ubiquitin Interacting Motif, UIM），其特征在于携带保守序列特征，且常存在于多结构域蛋白质中。
带有内在无序区域的多结构域蛋白质可介导与多种结合伴侣的相互作用，进而协调调控多样化的细胞通路。这类无序区域中往往嵌入有短线性结合基序，在调控蛋白质功能中发挥关键作用。
本研究中，我们利用分子动力学模拟与核磁共振（NMR）化学位移分析了UIM的结构倾向。尽管X射线晶体学（X-crystallography）所呈现的UIM结构图景为稳定的螺旋构象，但我们的研究表明，UIM同时兼具螺旋构象与内在无序构象。本研究结果揭示了一类全新的无序UIM，该类基序以共济失调蛋白-3（ataxin-3）某一亚型的C端结构域以及一组泛素特异性蛋白酶（ubiquitin-specific proteases）为典型代表。
有趣的是，UIM并非仅能结合泛素：它们还可作为招募其他相互作用因子的位点，例如帕金蛋白（parkin）与热休克蛋白Hsc70-4。无序UIM可为其宿主蛋白提供多功能性与全新功能，为相关蛋白质相互作用组的研究开辟了新方向。