ArticleNature structural & molecular biology2024
Structural mechanisms of autoinhibition and substrate recognition by the ubiquitin ligase HACE1.
Article in Nature structural & molecular biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 20 citations in OpenAlex.
- Integrated LiP-MS and quantitative proteomics reveal coordinated alterations in protein conformation and expression across tumor and peritumoral regions in hepatocellular carcinoma.Scientific reports · 2026Article
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- Degrons and degradation signals beyond short linear motifs.Nature chemical biology · 2026Review
- Structure and mechanism of the HECT ligase HECTD3.Nature communications · 2026Article
- Structure and mechanism of antiphage retron Eco2.Nature structural & molecular biology · 2026Article
- Mechanism of cooperative strigolactone perception by the MAX2 ubiquitin ligase-receptor-substrate complex.Nature communications · 2025Article
- State-of-the-Art and Future Directions in Structural Proteomics.Molecular & cellular proteomics : MCP · 2025Review
- Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1.Nature communications · 2025Article
- Ubiquitination of transcription factors in cancer: unveiling therapeutic potential.Molecular oncology · 2025Review
- How to Tell an N from an O: Controlling the Chemoselectivity of Methyltransferases.ACS catalysis · 2025Article
- Regulation of acetyl-CoA biosynthesis via an intertwined acetyl-CoA synthetase/acetyltransferase complex.Nature communications · 2025Article
- Understanding ubiquitination in neurodevelopment by integrating insights across space and time.Nature structural & molecular biology · 2025Review
- Protein semisynthesis reveals plasticity in HECT E3 ubiquitin ligase mechanisms.Nature chemistry · 2024Article
- Small molecule induced STING degradation facilitated by the HECT ligase HERC4.Nature communications · 2024Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ubiquitin ligases (E3s) are pivotal specificity determinants in the ubiquitin system by selecting substrates and decorating them with distinct ubiquitin signals. However, structure determination of the underlying, specific E3-substrate complexes has proven challenging owing to their transient nature. In particular, it is incompletely understood how members of the catalytic cysteine-driven class of HECT-type ligases (HECTs) position substrate proteins for modification. Here, we report a cryogenic electron microscopy (cryo-EM) structure of the full-length human HECT HACE1, along with solution-based conformational analyses by small-angle X-ray scattering and hydrogen-deuterium exchange mass spectrometry. Structure-based functional analyses in vitro and in cells reveal that the activity of HACE1 is stringently regulated by dimerization-induced autoinhibition. The inhibition occurs at the first step of the catalytic cycle and is thus substrate-independent. We use mechanism-based chemical crosslinking to reconstitute a complex of activated, monomeric HACE1 with its major substrate, RAC1, determine its structure by cryo-EM and validate the binding mode by solution-based analyses. Our findings explain how HACE1 achieves selectivity in ubiquitinating the active, GTP-loaded state of RAC1 and establish a framework for interpreting mutational alterations of the HACE1-RAC1 interplay in disease. More broadly, this work illuminates central unexplored aspects in the architecture, conformational dynamics, regulation and specificity of full-length HECTs.
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