ArticleThe Journal of biological chemistry2009
The signature 3-O-sulfo group of the anticoagulant heparin sequence is critical for heparin binding to antithrombin but is not required for allosteric activation.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 43 citations in OpenAlex.
- Polymers for Disrupting Protein-Protein Interactions: Where Are We and Where Should We Be?Biomacromolecules · 2024Review
- Targeting heparan sulfate-protein interactions with oligosaccharides and monoclonal antibodies.Frontiers in molecular biosciences · 2023Review
- Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function.Matrix biology plus · 2022Review
- Thermodynamic Affinity and Nature of Forces Defining Glycosaminoglycan-Protein Systems Using Fluorescence Spectroscopy.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Sulfated polysaccharide directs therapeutic angiogenesis via endogenous VEGF secretion of macrophages.Science advances · 2021Article
- Glypicans and Heparan Sulfate in Synaptic Development, Neural Plasticity, and Neurological Disorders.Frontiers in neural circuits · 2021Review
- Characterization and engineering of S100A12-heparan sulfate interactions.Glycobiology · 2020Article
- Elucidating the Interactions Between Heparin/Heparan Sulfate and SARS-CoV-2-Related Proteins-An Important Strategy for Developing Novel Therapeutics for the COVID-19 Pandemic.Frontiers in molecular biosciences · 2020Review
- Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα.Blood advances · 2019Article
- Domains with highest heparan sulfate-binding affinity reside at opposite ends in BMP2/4The Journal of biological chemistry · 2018Article
- Cooperative Interactions of Three Hotspot Heparin Binding Residues Are Critical for Allosteric Activation of Antithrombin by Heparin.Biochemistry · 2018Article
- Recombinant Heparin-New Opportunities.Frontiers in medicine · 2018Review
- Insights into the role of 3-O-sulfotransferase in heparan sulfate biosynthesis.Organic & biomolecular chemistry · 2017Article
- A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGFNature chemistry · 2017Article
- Blocking inhibition of prothrombinase by tissue factor pathway inhibitor alpha: a procoagulant property of heparins.British journal of haematology · 2016Article
- Investigating changes in the gas-phase conformation of Antithrombin III upon binding of Arixtra using traveling wave ion mobility spectrometry (TWIMS).The Analyst · 2015Article
- Heparan sulfate 3-O-sulfation: a rare modification in search of a function.Matrix biology : journal of the International Society for Matrix Biology · 2014Review
- Demystifying heparan sulfate-protein interactions.Annual review of biochemistry · 2014Review
- Probing structural selectivity of synthetic heparin binding to Stabilin protein receptors.The Journal of biological chemistry · 2012Article
- Exploiting enzyme specificities in digestions of chondroitin sulfates A and C: production of well-defined hexasaccharides.Glycobiology · 2012Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Heparin and heparan sulfate glycosaminoglycans allosterically activate the serpin, antithrombin, by binding through a specific pentasaccharide sequence containing a critical 3-O-sulfo group. To elucidate the role of the 3-O-sulfo group in the activation mechanism, we compared the effects of deleting the 3-O-sulfo group or mutating the Lys(114) binding partner of this group on antithrombin-pentasaccharide interactions by equilibrium binding and rapid kinetic analyses. Binding studies over a wide range of ionic strength and pH showed that loss of the 3-O-sulfo group caused a massive approximately 60% loss in binding energy for the antithrombin-pentasaccharide interaction due to the disruption of a cooperative network of ionic and nonionic interactions. Despite this affinity loss, the 3-O-desulfonated pentasaccharide retained the ability to induce tryptophan fluorescence changes and to enhance factor Xa reactivity in antithrombin, indicative of normal conformational activation. Rapid kinetic studies showed that loss of the 3-O-sulfo group affected both the ability of the pentasaccharide to recognize native antithrombin and its ability to preferentially bind and stabilize activated antithrombin. By contrast, mutation of Lys(114) solely affected the preferential interaction of the pentasaccharide with activated antithrombin. These findings demonstrate that the 3-O-sulfo group functions as a key determinant of heparin pentasaccharide activation of antithrombin both by contributing to the Lys(114)-independent recognition of native antithrombin and by triggering a Lys(114)-dependent induced fit interaction with activated antithrombin that locks the serpin in the activated state.
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Registered trials
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.