ArticleProceedings of the National Academy of Sciences of the United States of America2019
Crystal structure and activity-based labeling reveal the mechanisms for linkage-specific substrate recognition by deubiquitinase USP9X.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 59 citations in OpenAlex.
- Global analysis of cancer cell responses to USP9X inhibition.The EMBO journal · 2026Article
- Chaperone-Mediated Autophagic Degradation of USP9X in Macrophages Exacerbates Postmyocardial Infarction Inflammation and Cardiac Dysfunction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- From Covalent Traps to Fluorescent Beacons: The Expanding Arsenal of Chemical Probes for Studying Ubiquitin and Ubiquitin-Like Proteins.Angewandte Chemie (International ed. in English) · 2026Review
- CMA-mediated USP9X degradation promotes SHH medulloblastoma progression by facilitating SUFU ubiquitination.Clinical and translational medicine · 2026Article
- Thioether-mediated protein ubiquitination in constructing affinity- and activity-based ubiquitinated protein probes.Nature protocols · 2025Review
- USP45 Represses Melanoma Development by Deubiquitinating and Stabilizing Tumor Suppressor MRGPRF.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.Nature structural & molecular biology · 2025Article
- Emerging tools and methods to study cell signalling mediated by branched ubiquitin chains.Biochemical Society transactions · 2025Review
- USP7 V517F mutation as a mechanism of inhibitor resistance.Nature communications · 2025Article
- Article
- Characteristic craniofacial defects associated with a novel USP9X truncation mutation.Human genome variation · 2024Article
- Roles of USP9X in cellular functions and tumorigenesis (Review).Oncology letters · 2023Review
- The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes.Nature communications · 2023Article
- Triubiquitin Probes for Identification of Reader and Eraser Proteins of Branched Polyubiquitin Chains.ACS chemical biology · 2023Article
- Neutron-encoded diubiquitins to profile linkage selectivity of deubiquitinating enzymes.Nature communications · 2023Article
- Review
- In-Plate Chemical Synthesis of Isopeptide-Linked SUMOylated Peptide Fluorescence Polarization Reagents for High-Throughput Screening of SENP Preferences.Chembiochem : a European journal of chemical biology · 2023Article
- The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders.Biological psychiatry · 2022Review
- Development and validation of a novel ubiquitination-related gene prognostic signature based on tumor microenvironment for colon cancer.Translational cancer research · 2022Article
- Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site.Science advances · 2022Article
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Authors and funding
11 authors at 3 institutions in 3 countries.
Funding
Abstract
USP9X is a conserved deubiquitinase (DUB) that regulates multiple cellular processes. Dysregulation of USP9X has been linked to cancers and X-linked intellectual disability. Here, we report the crystal structure of the USP9X catalytic domain at 2.5-Å resolution. The structure reveals a canonical USP-fold comprised of fingers, palm, and thumb subdomains, as well as an unusual β-hairpin insertion. The catalytic triad of USP9X is aligned in an active configuration. USP9X is exclusively active against ubiquitin (Ub) but not Ub-like modifiers. Cleavage assays with di-, tri-, and tetraUb chains show that the USP9X catalytic domain has a clear preference for K11-, followed by K63-, K48-, and K6-linked polyUb chains. Using a set of activity-based diUb and triUb probes (ABPs), we demonstrate that the USP9X catalytic domain has an exo-cleavage preference for K48- and endo-cleavage preference for K11-linked polyUb chains. The structure model and biochemical data suggest that the USP9X catalytic domain harbors three Ub binding sites, and a zinc finger in the fingers subdomain and the β-hairpin insertion both play important roles in polyUb chain processing and linkage specificity. Furthermore, unexpected labeling of a secondary, noncatalytic cysteine located on a blocking loop adjacent to the catalytic site by K11-diUb ABP implicates a previously unreported mechanism of polyUb chain recognition. The structural features of USP9X revealed in our study are critical for understanding its DUB activity. The new Ub-based ABPs form a set of valuable tools to understand polyUb chain processing by the cysteine protease class of DUBs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.