Structural, in silico, and functional analysis of a Disabled-2-derived peptide for recognition of sulfatides

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dc.contributor.authorSong, Weien
dc.contributor.authorGottschalk, Carter J.en
dc.contributor.authorTang, Tuo-Xianen
dc.contributor.authorBiscardi, Andrewen
dc.contributor.authorEllena, Jeffrey F.en
dc.contributor.authorFinkielstein, Carla V.en
dc.contributor.authorBrown, Anne M.en
dc.contributor.authorCapelluto, Daniel G. S.en
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.contributor.departmentCenter for Soft Matter and Biological Physicsen
dc.contributor.departmentUniversity Librariesen
dc.contributor.departmentBiochemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.date.accessioned2020-10-07T17:45:17Zen
dc.date.available2020-10-07T17:45:17Zen
dc.date.issued2020-08-11en
dc.description.abstractDisabled-2 (Dab2) is an adaptor protein that regulates the extent of platelet aggregation by two mechanisms. In the first mechanism, Dab2 intracellularly downregulates the integrin alpha (IIb)beta (3) receptor, converting it to a low affinity state for adhesion and aggregation processes. In the second mechanism, Dab2 is released extracellularly and interacts with the pro-aggregatory mediators, the integrin alpha (IIb)beta (3) receptor and sulfatides, blocking their association to fibrinogen and P-selectin, respectively. Our previous research indicated that a 35-amino acid region within Dab2, which we refer to as the sulfatide-binding peptide (SBP), contains two potential sulfatide-binding motifs represented by two consecutive polybasic regions. Using molecular docking, nuclear magnetic resonance, lipid-binding assays, and surface plasmon resonance, this work identifies the critical Dab2 residues within SBP that are responsible for sulfatide binding. Molecular docking suggested that a hydrophilic region, primarily mediated by R42, is responsible for interaction with the sulfatide headgroup, whereas the C-terminal polybasic region contributes to interactions with acyl chains. Furthermore, we demonstrated that, in Dab2 SBP, R42 significantly contributes to the inhibition of platelet P-selectin surface expression. The Dab2 SBP residues that interact with sulfatides resemble those described for sphingolipid-binding in other proteins, suggesting that sulfatide-binding proteins share common binding mechanisms.en
dc.description.notesWe thank Dr. Janet Webster for critical reading of the manuscript. This project was supported by the Virginia Academy of Science, the Institute for Critical Technology and Applied Science (ICTAS) at Virginia Tech, the 4-VA Collaborative Research Program (to D.G.S.C.), and the National Science Foundation (MCB-1517298) (to C.V.F). W.S. was supported by an ICTAS pre-doctoral fellowship.en
dc.description.sponsorshipVirginia Academy of Science; Institute for Critical Technology and Applied Science (ICTAS) at Virginia Tech; 4-VA Collaborative Research Program; National Science FoundationNational Science Foundation (NSF) [MCB-1517298]; ICTAS pre-doctoral fellowshipen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-020-70478-0en
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.other13520en
dc.identifier.pmid32782308en
dc.identifier.urihttp://hdl.handle.net/10919/100300en
dc.identifier.volume10en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleStructural, in silico, and functional analysis of a Disabled-2-derived peptide for recognition of sulfatidesen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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