Sulfatides Partition Disabled-2 in Response to Platelet Activation

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dc.contributor.authorDrahos, Karen E.en
dc.contributor.authorWelsh, John D.en
dc.contributor.authorFinkielstein, Carla V.en
dc.contributor.authorCapelluto, Daniel G. S.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2018-11-14T14:44:43Zen
dc.date.available2018-11-14T14:44:43Zen
dc.date.issued2009-11-24en
dc.description.abstractBackground Platelets contact each other at the site of vascular injury to stop bleeding. One negative regulator of platelet aggregation is Disabled-2 (Dab2), which is released to the extracellular surface upon platelet activation. Dab2 inhibits platelet aggregation through its phosphotyrosine-binding (PTB) domain by competing with fibrinogen for αIIbβ3 integrin receptor binding by an unknown mechanism. Methodology/Principal Findings Using protein-lipid overlay and liposome-binding assays, we identified that the N-terminal region of Dab2, including its PTB domain (N-PTB), specifically interacts with sulfatides. Moreover, we determined that such interaction is mediated by two conserved basic motifs with a dissociation constant (Kd) of 0.6 µM as estimated by surface plasmon resonance (SPR) analysis. In addition, liposome-binding assays combined with mass spectroscopy studies revealed that thrombin, a strong platelet agonist, cleaved N-PTB at a site located between the basic motifs, a region that becomes protected from thrombin cleavage when bound to sulfatides. Sulfatides on the platelet surface interact with coagulation proteins, playing a major role in haemostasis. Our results show that sulfatides recruit N-PTB to the platelet surface, sequestering it from integrin receptor binding during platelet activation. This is a transient recruitment that follows N-PTB internalization by an actin-dependent process. Conclusions/Significance Our experimental data support a model where two pools of Dab2 co-exist at the platelet surface, in both sulfatide- and integrin receptor-bound states, and their balance controls the extent of the clotting response.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0008007en
dc.identifier.eissn1932-6203en
dc.identifier.issue11en
dc.identifier.othere8007en
dc.identifier.pmid19956625en
dc.identifier.urihttp://hdl.handle.net/10919/85840en
dc.identifier.volume4en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleSulfatides Partition Disabled-2 in Response to Platelet Activationen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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