Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse Platelets
Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused o...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/2/423 |
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| author | Chao Han Pengxuan Ren Medina Mamtimin Linus Kruk Edita Sarukhanyan Chenyu Li Hans-Joachim Anders Thomas Dandekar Irena Krueger Margitta Elvers Silvia Goebel Kristin Adler Götz Münch Thomas Gudermann Attila Braun Elmina Mammadova-Bach |
| author_facet | Chao Han Pengxuan Ren Medina Mamtimin Linus Kruk Edita Sarukhanyan Chenyu Li Hans-Joachim Anders Thomas Dandekar Irena Krueger Margitta Elvers Silvia Goebel Kristin Adler Götz Münch Thomas Gudermann Attila Braun Elmina Mammadova-Bach |
| author_sort | Chao Han |
| collection | DOAJ |
| description | Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused on site-specific targeting of GPVI. Using computational modeling and bioinformatics, we analyzed collagen- and CRP-binding surfaces of GPVI monomers and dimers, and compared the interacting surfaces with other mammalian GPVI isoforms. We could predict a minimal collagen-binding epitope of GPVI dimer and designed an EA-20 antibody that recognizes a linear epitope of this surface. Using platelets and whole blood samples donated from wild-type and humanized GPVI transgenic mice and also humans, our experimental results show that the EA-20 antibody inhibits platelet adhesion and aggregation in response to collagen and CRP, but not to fibrin. The EA-20 antibody also prevents thrombus formation in whole blood, on the collagen-coated surface, in arterial flow conditions. We also show that EA-20 does not influence GPVI clustering or receptor shedding. Therefore, we propose that blockade of this minimal collagen-binding epitope of GPVI with the EA-20 antibody could represent a new anti-thrombotic approach by inhibiting specific interactions between GPVI and the collagen matrix. |
| first_indexed | 2024-03-11T09:07:16Z |
| format | Article |
| id | doaj.art-baa6ba13cc5e43369b4b0d501f8dc336 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T09:07:16Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-baa6ba13cc5e43369b4b0d501f8dc3362023-11-16T19:18:00ZengMDPI AGBiomedicines2227-90592023-02-0111242310.3390/biomedicines11020423Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse PlateletsChao Han0Pengxuan Ren1Medina Mamtimin2Linus Kruk3Edita Sarukhanyan4Chenyu Li5Hans-Joachim Anders6Thomas Dandekar7Irena Krueger8Margitta Elvers9Silvia Goebel10Kristin Adler11Götz Münch12Thomas Gudermann13Attila Braun14Elmina Mammadova-Bach15Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, GermanySchool of Life Science and Technology, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, ChinaWalther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, GermanyWalther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, GermanyDepartment of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, GermanyDivision of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, GermanyDivision of Nephrology, Department of Medicine IV, Hospital of the Ludwig-Maximilian-University, 80336 Munich, GermanyDepartment of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, GermanyDepartment of Vascular and Endovascular Surgery, Heinrich-Heine University Medical Center, 40225 Düsseldorf, GermanyDepartment of Vascular and Endovascular Surgery, Heinrich-Heine University Medical Center, 40225 Düsseldorf, GermanyAdvanceCOR GmbH, 82152 Martinsried, GermanyAdvanceCOR GmbH, 82152 Martinsried, GermanyAdvanceCOR GmbH, 82152 Martinsried, GermanyWalther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, GermanyWalther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, GermanyWalther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian-University, 80336 Munich, GermanyGlycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused on site-specific targeting of GPVI. Using computational modeling and bioinformatics, we analyzed collagen- and CRP-binding surfaces of GPVI monomers and dimers, and compared the interacting surfaces with other mammalian GPVI isoforms. We could predict a minimal collagen-binding epitope of GPVI dimer and designed an EA-20 antibody that recognizes a linear epitope of this surface. Using platelets and whole blood samples donated from wild-type and humanized GPVI transgenic mice and also humans, our experimental results show that the EA-20 antibody inhibits platelet adhesion and aggregation in response to collagen and CRP, but not to fibrin. The EA-20 antibody also prevents thrombus formation in whole blood, on the collagen-coated surface, in arterial flow conditions. We also show that EA-20 does not influence GPVI clustering or receptor shedding. Therefore, we propose that blockade of this minimal collagen-binding epitope of GPVI with the EA-20 antibody could represent a new anti-thrombotic approach by inhibiting specific interactions between GPVI and the collagen matrix.https://www.mdpi.com/2227-9059/11/2/423GPVIcollagenblood plateletsthrombosisanti-thrombotic therapies |
| spellingShingle | Chao Han Pengxuan Ren Medina Mamtimin Linus Kruk Edita Sarukhanyan Chenyu Li Hans-Joachim Anders Thomas Dandekar Irena Krueger Margitta Elvers Silvia Goebel Kristin Adler Götz Münch Thomas Gudermann Attila Braun Elmina Mammadova-Bach Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse Platelets Biomedicines GPVI collagen blood platelets thrombosis anti-thrombotic therapies |
| title | Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse Platelets |
| title_full | Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse Platelets |
| title_fullStr | Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse Platelets |
| title_full_unstemmed | Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse Platelets |
| title_short | Minimal Collagen-Binding Epitope of Glycoprotein VI in Human and Mouse Platelets |
| title_sort | minimal collagen binding epitope of glycoprotein vi in human and mouse platelets |
| topic | GPVI collagen blood platelets thrombosis anti-thrombotic therapies |
| url | https://www.mdpi.com/2227-9059/11/2/423 |
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