ArticleProtein science : a publication of the Protein Society2021
Previously uncharacterized interactions between the folded and intrinsically disordered domains impart asymmetric effects on UBQLN2 phase separation.
Article in Protein science : a publication of the Protein Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.bioRxiv : the preprint server for biology · 2026Article
- Conformational landscapes resolved by ion mobility mass spectrometry reveal mechanisms of polyubiquitin-controlled phase separation.Chemical science · 2026Article
- STI1 domains coordinate partitioning of UBQLN2 into stress-induced condensates.bioRxiv : the preprint server for biology · 2026Article
- STI1 domain engages transient helices to mediate Dsk2 phase separation and proteasome condensation.The EMBO journal · 2026Article
- Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation.The EMBO journal · 2025Article
- The formation of chaperone-rich GET bodies depends on the tetratricopeptide repeat region of Sgt2 and is reversed by NADH.Journal of cell science · 2025Article
- Structured protein domains enter the spotlight: modulators of biomolecular condensate form and function.Trends in biochemical sciences · 2025Review
- Short disordered termini and proline-rich domain are major regulators of UBQLN1/2/4 phase separation.Biophysical journal · 2024Article
- Proteasome condensate formation is driven by multivalent interactions with shuttle factors and ubiquitin chains.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The molecular basis for cellular function of intrinsically disordered protein regions.Nature reviews. Molecular cell biology · 2024Review
- Structural biases in disordered proteins are prevalent in the cell.Nature structural & molecular biology · 2024Article
- A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP-43 and modulates its phase behavior.Protein science : a publication of the Protein Society · 2024Article
- Polyubiquitin ligand-induced phase transitions are optimized by spacing between ubiquitin units.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Ion Mobility Mass Spectrometry Unveils Global Protein Conformations in Response to Conditions that Promote and Reverse Liquid-Liquid Phase Separation.Journal of the American Chemical Society · 2023Article
- Global Discovery of Covalent Modulators of Ribonucleoprotein Granules.Journal of the American Chemical Society · 2023Article
- Decoding optimal ligand design for multicomponent condensates.bioRxiv : the preprint server for biology · 2023Article
- E6AP AZUL interaction with UBQLN1/2 in cells, condensates, and an AlphaFold-NMR integrated structure.Structure (London, England : 1993) · 2023Article
- Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer's disease and amyotrophic lateral sclerosis.Frontiers in molecular biosciences · 2023Review
- Principles Governing the Phase Separation of Multidomain Proteins.Biochemistry · 2022Review
- RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control.Cellular and molecular life sciences : CMLS · 2022Article
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Abstract
Shuttle protein UBQLN2 functions in protein quality control (PQC) by binding to proteasomal receptors and ubiquitinated substrates via its N-terminal ubiquitin-like (UBL) and C-terminal ubiquitin-associated (UBA) domains, respectively. Between these two folded domains are low-complexity STI1-I and STI1-II regions, connected by disordered linkers. The STI1 regions bind other components, such as HSP70, that are important to the PQC functions of UBQLN2. We recently determined that the STI1-II region enables UBQLN2 to undergo liquid-liquid phase separation (LLPS) to form liquid droplets in vitro and biomolecular condensates in cells. However, how the interplay between the folded (UBL/UBA) domains and the intrinsically disordered regions mediates phase separation is largely unknown. Using engineered domain deletion constructs, we found that removing the UBA domain inhibits UBQLN2 LLPS while removing the UBL domain enhances LLPS, suggesting that UBA and UBL domains contribute asymmetrically in modulating UBQLN2 LLPS. To explain these differential effects, we interrogated the interactions that involve the UBA and UBL domains across the entire UBQLN2 molecule using nuclear magnetic resonance spectroscopy. To our surprise, aside from well-studied canonical UBL:UBA interactions, there also exist moderate interactions between the UBL and several disordered regions, including STI1-I and residues 555-570, the latter of which is a known contributor to UBQLN2 LLPS. Our findings are essential for the understanding of both the molecular driving forces of UBQLN2 LLPS and the effects of ligand binding to UBL, UBA, or disordered regions on the phase behavior and physiological functions of UBQLN2.
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