ArticleThe Journal of biological chemistry2012
Unique disulfide bonds in epidermal growth factor (EGF) domains of β3 affect structure and function of αIIbβ3 and αvβ3 integrins in different manner.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 63 citations in OpenAlex.
- Single-molecule kinetic exploration of functional sub-states in an evolving phosphotriesterase.Nature communications · 2026Article
- Allosteric Disulfide Bridges in Integrins: The Molecular Switches of Redox Regulation of Integrin-Mediated Cell Functions.Antioxidants (Basel, Switzerland) · 2025Review
- Extracellular PDI in thrombosis and vascular injury.Thrombosis journal · 2025Review
- Recent advances in vascular thiol isomerases: insights into structures, functions in thrombosis and antithrombotic inhibitor development.Thrombosis journal · 2025Review
- Recent advances in vascular thiol isomerases and redox systems in platelet function and thrombosis.Journal of thrombosis and haemostasis : JTH · 2024Review
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- Vascular endothelial ERp72 is involved in the inflammatory response in a rat model of skeletal muscle injury.Molecular medicine reports · 2021Article
- Naturally occurring point mutation Cys460Trp located in the I-EGF1 domain of integrin β3 alters the binding of some anti-HPA-1a antibodies.Transfusion · 2020Article
- Article
- Modifications of disulfide bonds in breast cancer cell migration and invasiveness.American journal of cancer research · 2019Article
- Reduction of leucocyte cell surface disulfide bonds during immune activation is dynamic as revealed by a quantitative proteomics workflow (SH-IQ).Open biology · 2018Article
- Regulatory role of thiol isomerases in thrombus formation.Expert review of hematology · 2018Review
- The importance of N-glycosylation on βScientific reports · 2017Article
- From structure to redox: The diverse functional roles of disulfides and implications in disease.Proteomics · 2017Review
- RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye.Autophagy · 2017Article
- Article
- Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia.Haematologica · 2016Article
- αIIbβ3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Redox-relevant aspects of the extracellular matrix and its cellular contacts via integrins.Antioxidants & redox signaling · 2014Review
- Thiol isomerases in thrombus formation.Circulation research · 2014Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The β3 subunit of αIIbβ3 and αvβ3 integrins contains four epidermal growth factor (EGF)-like domains. Each domain harbors four disulfide bonds of which one is unique for integrins. We previously discerned a regulatory role of the EGF-4 Cys-560-Cys-583 unique bond for αIIbβ3 activation. In this study we further investigated the role of all four integrin unique bonds in both αIIbβ3 and αvβ3. We created β3 mutants harboring serine substitutions of each or both cysteines that disrupt the four unique bonds (Cys-437-Cys-457 in EGF-1, Cys-473-Cys-503 in EGF-2, Cys-523-Cys-544 in EGF-3, and Cys-560-Cys-583 in EGF-4) and transfected them into baby hamster kidney cells together with normal αv or αIIb. Flow cytometry was used to measure surface expression of αIIbβ3 and αvβ3 and their activity state by soluble fibrinogen binding. Most cysteine substitutions caused similarly reduced surface expression of both receptors. Disrupting all four unique disulfide bonds by single cysteine substitutions resulted in variable constitutive activation of αIIbβ3 and αvβ3. In contrast, whereas double C437S/C457S and C473S/C503S mutations yielded constitutively active αIIbβ3 and αvβ3, the C560S/C583S mutation did not, and the C523S/C544S mutation only yielded constitutively active αIIbβ3. Activation of C523S/C544S αvβ3 mutant by activating antibody and dithiothreitol was also impaired. Molecular dynamics of C523S/C544S β3 in αIIbβ3 but not in αvβ3 displayed an altered stable conformation. Our findings indicate that unique disulfide bonds in β3 differently affect the function of αIIbβ3 and αvβ3 and suggest a free sulfhydryl-dependent regulatory role for Cys-560-Cys-583 in both αIIbβ3 and αvβ3 and for Cys-523-Cys-544 only in αvβ3.
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