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

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 J. Bridge, Christoph Wierling*, Steve P. Watson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Article numbere1010708
JournalPLoS Computational Biology
Volume18
Issue number11
Early online date28 Nov 2022
DOIs
Publication statusPublished - 28 Nov 2022

Keywords

  • Biology and life sciences
  • Computer and information sciences
  • Medicine and health sciences
  • Physical sciences
  • Research Article
  • Research and analysis methods

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