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Interspecies differences in protein expression do not impact the spatiotemporal regulation of GPVI mediated activation

Dunster, Joanne, Unsworth, Amanda ORCID logoORCID: https://orcid.org/0000-0003-3809-5984, Bye, Alexander, Haining, Elizabeth, Sowa, Marcin, Ying, Di, Sage, Tanya, Pallini, Chiara, Pike, Jeremy, Hardy, Alexander, Nieswandt, Bernard, Garcia, A, Watson, Stephen, Poulter, Natalie, Gibbins, Jonathan and Pollitt, Alice (2020) Interspecies differences in protein expression do not impact the spatiotemporal regulation of GPVI mediated activation. Journal of Thrombosis and Haemostasis, 18 (2). pp. 485-496. ISSN 1538-7933

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Background Accurate protein quantification is a vital prerequisite for generating meaningful predictions when using systems biology approaches, a method that is increasingly being used to unravel the complexities of sub cellular interactions and as part of the drug discovery process. Quantitative proteomics, flow cytometry and western blotting have been extensively used to define human platelet protein copy numbers, yet for mouse platelets, a model widely used for platelet research, evidence is largely limited to a single proteomic dataset in which the total amount of proteins were generally comparatively higher than those found in human platelets. Objectives To investigate the functional implications of discrepancies between levels of mouse and human proteins in the GPVI signalling pathway using a systems pharmacology model of GPVI Methods The protein copy number of mouse platelet receptors was determined using flow cytometry. The Virtual Platelet, a mathematical model of Glycoprotein VI (GPVI) signalling, was used to determine the consequences of protein copy number differences observed between human and mouse platelets. Results and conclusion Despite the small size of mouse platelets compared to human platelets they possessed a greater density of surface receptors alongside a higher concentration of intracellular signalling proteins. Surprisingly the predicted temporal profile of Syk activity was similar in both species with predictions supported experimentally. Super resolution microscopy demonstrates that the spatial distribution of Syk is similar between species, suggesting that the spatial distribution of receptors and signalling molecules, rather than their copy number, is important for signalling pathway regulation.

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