ArticleThe Journal of biological chemistry2019
Did evolution create a flexible ligand-binding cavity in the urokinase receptor through deletion of a plesiotypic disulfide bond?
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 16 citations in OpenAlex.
- Optimization and production of a GLP-grade recombinant Sm29 vaccine against schistosomiasis: From expression to preclinical assessment.PLoS neglected tropical diseases · 2026Article
- uPAR/suPAR Signaling and Organ Crosstalk in Cardiovascular-Kidney-Metabolic Syndrome.Circulation research · 2026Review
- Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator.Biomedicines · 2024Review
- Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Conformationally Restricted Glycopeptide Backbone Inhibits Gas-Phase H/D Scrambling between Glycan and Peptide Moieties.Journal of the American Chemical Society · 2023Article
- Targeted imaging of uPAR expression in vivo with cyclic AE105 variants.Scientific reports · 2023Article
- Crystal structure and cellular functions of uPAR dimer.Nature communications · 2022Article
- The Urokinase Receptor (uPAR) as a "Trojan Horse" in Targeted Cancer Therapy: Challenges and Opportunities.Cancers · 2021Review
- The intrinsic instability of the hydrolase domain of lipoprotein lipase facilitates its inactivation by ANGPTL4-catalyzed unfolding.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention.Frontiers in cell and developmental biology · 2021Review
- GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity.Frontiers in cell and developmental biology · 2021Review
- Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Evolution and Medical Significance of LU Domain-Containing Proteins.International journal of molecular sciences · 2019Review
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The urokinase receptor (uPAR) is a founding member of a small protein family with multiple Ly6/uPAR (LU) domains. The motif defining these LU domains contains five plesiotypic disulfide bonds stabilizing its prototypical three-fingered fold having three protruding loops. Notwithstanding the detailed knowledge on structure-function relationships in uPAR, one puzzling enigma remains unexplored. Why does the first LU domain in uPAR (DI) lack one of its consensus disulfide bonds, when the absence of this particular disulfide bond impairs the correct folding of other single LU domain-containing proteins? Here, using a variety of contemporary biophysical methods, we found that reintroducing the two missing half-cystines in uPAR DI caused the spontaneous formation of the corresponding consensus 7-8 LU domain disulfide bond. Importantly, constraints due to this cross-link impaired (i) the binding of uPAR to its primary ligand urokinase and (ii) the flexible interdomain assembly of the three LU domains in uPAR. We conclude that the evolutionary deletion of this particular disulfide bond in uPAR DI may have enabled the assembly of a high-affinity urokinase-binding cavity involving all three LU domains in uPAR. Of note, an analogous neofunctionalization occurred in snake venom α-neurotoxins upon loss of another pair of the plesiotypic LU domain half-cystines. In summary, elimination of the 7-8 consensus disulfide bond in the first LU domain of uPAR
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