Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif

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dc.contributor.authorZhao, Xiaolinen
dc.contributor.authorXiong, Wenen
dc.contributor.authorXiao, Shuyanen
dc.contributor.authorTang, Tuo-Xianen
dc.contributor.authorEllena, Jeffrey F.en
dc.contributor.authorArmstrong, Geoffrey S.en
dc.contributor.authorFinkielstein, Carla V.en
dc.contributor.authorCapelluto, Daniel G. S.en
dc.contributor.departmentCenter for Soft Matter and Biological Physicsen
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2017-06-13T12:35:06Zen
dc.date.available2017-06-13T12:35:06Zen
dc.date.issued2017-02-22en
dc.description.abstractPathogen-activated Toll-like receptors (TLRs), such as TLR2 and TLR4, dimerize and move laterally across the plasma membrane to phosphatidylinositol (4,5)-bisphosphate-enriched domains. At these sites, TLRs interact with the TIR domain-containing adaptor protein (TIRAP), triggering a signaling cascade that leads to innate immune responses. Membrane recruitment of TIRAP is mediated by its phosphoinositide (PI)-binding motif (PBM). We show that TIRAP PBM transitions from a disordered to a helical conformation in the presence of either zwitterionic micelles or monodispersed PIs. TIRAP PBM bound PIs through basic and nonpolar residues with high affinity, favoring a more ordered structure. TIRAP is phosphorylated at Thr28 within its PBM, which leads to its ubiquitination and degradation. We demonstrate that phosphorylation distorts the helical structure of TIRAP PBM, reducing PI interactions and cell membrane targeting. Our study provides the basis for TIRAP membrane insertion and the mechanism by which it is removed from membranes to avoid sustained innate immune responses.en
dc.description.versionPublished versionen
dc.format.extent? - ? (12) page(s)en
dc.identifier.doihttps://doi.org/10.1038/srep43043en
dc.identifier.issn2045-2322en
dc.identifier.orcidFinkielstein, CV [0000-0002-8417-4643]en
dc.identifier.orcidCapelluto, DGS [0000-0002-0412-4508]en
dc.identifier.urihttp://hdl.handle.net/10919/78033en
dc.identifier.volume7en
dc.languageEnglishen
dc.publisherNature Publishing Groupen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000394530800001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectscience and technologyen
dc.subjectmyd88 adapter-likeen
dc.subjectpleckstrin homology domainen
dc.subjectsignal-transductionen
dc.subjectsubcellular sitesen
dc.subjectreceptoren
dc.subjectkinaseen
dc.subjectrecognitionen
dc.subjecttlr4en
dc.subjectnmren
dc.titleMembrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motifen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/Scienceen
pubs.organisational-group/Virginia Tech/Science/Biological Sciencesen
pubs.organisational-group/Virginia Tech/Science/COS T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Fralin Affiliated Facultyen

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