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Platelet activators stimulate post-translational modification of signalling proteins to change their activity or their molecular interactions leading to signal propagation. One covalent modification is attachment of the small protein ubiquitin to lysine residues in target proteins. Modification by ubiquitin can either target proteins for degradation by the proteasome or act as a scaffold for other proteins. Pharmacological inhibition of deubiquitylases or the proteasome inhibition of platelet activation by collagen, demonstrating a role for ubiquitylation, but relatively few substrates for ubiquitin have been identified and the molecular basis of inhibition is not established. Here, we report the ubiquitome of human platelets and changes in ubiquitylated proteins following stimulation by collagen-related peptide (CRP-XL). Using platelets from six individuals over three independent experiments, we identified 1,634 ubiquitylated peptides derived from 691 proteins, revealing extensive ubiquitylation in resting platelets. Note that 925 of these peptides show an increase of more than twofold following stimulation with CRP-XL. Multiple sites of ubiquitylation were identified on several proteins including Syk, filamin and integrin heterodimer sub-units. This work reveals extensive protein ubiquitylation during activation of human platelets and opens the possibility of novel therapeutic interventions targeting the ubiquitin machinery.

Original publication

DOI

10.1055/s-0038-1676344

Type

Journal article

Journal

Thromb Haemost

Publication Date

01/2019

Volume

119

Pages

104 - 116

Keywords

Blood Platelets, Flow Cytometry, Humans, Intracellular Signaling Peptides and Proteins, Lysine, Mass Spectrometry, P-Selectin, Platelet Activation, Platelet Membrane Glycoproteins, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Signal Transduction, Ubiquitin, Ubiquitination