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Experimental validation of computerised models of clustering of platelet glycoprotein receptors that signal via tandem SH2 domain proteins

Maqsood, Zahra; Clark, Joanne C.; Martin, Eleyna M.; Cheung, Yam Fung Hilaire; Morán, Luis A.; Watson, Sean E. T.; Pike, Jeremy A.; Di, Ying; Poulter, Natalie S.; Slater, Alexandre; Lange, Bodo M. H.; Nieswandt, Bernhard; Eble, Johannes A.; Tomlinson, Mike G.; Owen, Dylan M.; Stegner, David; Bridge, Lloyd J.; Wierling, Christoph; Watson, Steve P.

Experimental validation of computerised models of clustering of platelet glycoprotein receptors that signal via tandem SH2 domain proteins Thumbnail


Authors

Zahra Maqsood

Joanne C. Clark

Eleyna M. Martin

Yam Fung Hilaire Cheung

Luis A. Morán

Sean E. T. Watson

Jeremy A. Pike

Ying Di

Natalie S. Poulter

Alexandre Slater

Bodo M. H. Lange

Bernhard Nieswandt

Johannes A. Eble

Mike G. Tomlinson

Dylan M. Owen

David Stegner

Lloyd Bridge Lloyd.Bridge@uwe.ac.uk
Senior Lecturer in Mathematics

Christoph Wierling

Steve P. Watson



Abstract

The clustering of platelet glycoprotein receptors with cytosolic YxxL and YxxM motifs, including GPVI, CLEC-2 and PEAR1, triggers activation via phosphorylation of the conserved tyrosine residues and recruitment of the tandem SH2 (Src homology 2) domain effector proteins, Syk and PI 3-kinase. We have modelled the clustering of these receptors with monovalent, divalent and tetravalent soluble ligands and with transmembrane ligands based on the law of mass action using ordinary differential equations and agent-based modelling. The models were experimentally evaluated in platelets and transfected cell lines using monovalent and multivalent ligands, including novel nanobody-based divalent and tetravalent ligands, by fluorescence correlation spectroscopy. Ligand valency, receptor number, receptor dimerisation, receptor phosphorylation and a cytosolic tandem SH2 domain protein act in synergy to drive receptor clustering. Threshold concentrations of a CLEC-2-blocking antibody and Syk inhibitor act in synergy to block platelet aggregation. This offers a strategy for countering the effect of avidity of multivalent ligands and in limiting off-target effects.

Journal Article Type Article
Acceptance Date Nov 4, 2022
Online Publication Date Nov 28, 2022
Publication Date Nov 28, 2022
Deposit Date Dec 9, 2022
Publicly Available Date Dec 12, 2022
Journal PLoS Computational Biology
Print ISSN 1553-734X
Electronic ISSN 1553-7358
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 18
Issue 11
Article Number e1010708
DOI https://doi.org/10.1371/journal.pcbi.1010708
Keywords Computational Theory and Mathematics; Cellular and Molecular Neuroscience; Genetics; Molecular Biology; Ecology; Modeling and Simulation; Ecology, Evolution, Behavior and Systematics
Public URL https://uwe-repository.worktribe.com/output/10196043
Publisher URL https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1010708

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