Proteomics

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Changes in the human platelet protein ubiquitylation landscape following GPVI activation


ABSTRACT: 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 inhibits 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). We identified 1634 ubiquitylated peptides derived from 691 proteins, revealing extensive ubiquitylation in resting platelets. 925 of these peptides show an increase of more than 2-fold following stimulation with CRP-XL. Multiple sites of ubiquitylation were identified on a number of proteins including Syk, filamin and integrins. Adhesion and spreading on fibrinogen mediated by the major platelet integrin IIb3 is blocked by inhibition of deubiquitylases. This work reveals extensive protein ubiquitylation during activation of human platelets and opens the possibility of novel therapeutic interventions targeting the ubiquitin machinery.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Platelet, Platelet, Blood Cell

SUBMITTER: Benedikt Kessler  

LAB HEAD: Benedikt M Kessler

PROVIDER: PXD009072 | Pride | 2019-01-07

REPOSITORIES: Pride

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Publications

Human Platelet Protein Ubiquitylation and Changes following GPVI Activation.

Unsworth Amanda J AJ   Bombik Izabela I   Pinto-Fernandez Adan A   McGouran Joanna F JF   Konietzny Rebecca R   Zahedi René P RP   Watson Steve P SP   Kessler Benedikt M BM   Pears Catherine J CJ  

Thrombosis and haemostasis 20181231 1


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 ac  ...[more]

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