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dc.contributor.authorGordon, Wendy R.en_US
dc.contributor.authorVardar-Ulu, Didemen_US
dc.contributor.authorL'Heureux, Sarahen_US
dc.contributor.authorAshworth, Todden_US
dc.contributor.authorMalecki, Michael J.en_US
dc.contributor.authorSanchez-Irizarry, Cheryllen_US
dc.contributor.authorMcArthur, Debbie G.en_US
dc.contributor.authorHisten, Gavinen_US
dc.contributor.authorMitchell, Jennifer L.en_US
dc.contributor.authorAster, Jon C.en_US
dc.contributor.authorBlacklow, Stephen C.en_US
dc.date.accessioned2019-09-09T17:27:35Z
dc.date.available2019-09-09T17:27:35Z
dc.date.issued2009-08-24
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000269268300001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=6e74115fe3da270499c3d65c9b17d654
dc.identifier.citationWendy R Gordon, Didem Vardar-Ulu, Sarah L'Heureux, Todd Ashworth, Michael J Malecki, Cheryll Sanchez-Irizarry, Debbie G McArthur, Gavin Histen, Jennifer L Mitchell, Jon C Aster, Stephen C Blacklow. 2009. "Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2." PLOS ONE, Volume 4, Issue 8, pp. ? - ? (12). https://doi.org/10.1371/journal.pone.0006613
dc.identifier.issn1932-6203
dc.identifier.urihttps://hdl.handle.net/2144/37751
dc.description.abstractBACKGROUND: Notch receptors are normally cleaved during maturation by a furin-like protease at an extracellular site termed S1, creating a heterodimer of non-covalently associated subunits. The S1 site lies within a key negative regulatory region (NRR) of the receptor, which contains three highly conserved Lin12/Notch repeats and a heterodimerization domain (HD) that interact to prevent premature signaling in the absence of ligands. Because the role of S1 cleavage in Notch signaling remains unresolved, we investigated the effect of S1 cleavage on the structure, surface trafficking and ligand-mediated activation of human Notch1 and Notch2, as well as on ligand-independent activation of Notch1 by mutations found in human leukemia. PRINCIPAL FINDINGS: The X-ray structure of the Notch1 NRR after furin cleavage shows little change when compared with that of an engineered Notch1 NRR lacking the S1-cleavage loop. Likewise, NMR studies of the Notch2 HD domain show that the loop containing the S1 site can be removed or cleaved without causing a substantial change in its structure. However, Notch1 and Notch2 receptors engineered to resist S1 cleavage exhibit unexpected differences in surface delivery and signaling competence: S1-resistant Notch1 receptors exhibit decreased, but detectable, surface expression and ligand-mediated receptor activation, whereas S1-resistant Notch2 receptors are fully competent for cell surface delivery and for activation by ligands. Variable dependence on S1 cleavage also extends to T-ALL-associated NRR mutations, as common class 1 mutations display variable decrements in ligand-independent activation when introduced into furin-resistant receptors, whereas a class 2 mutation exhibits increased signaling activity. CONCLUSIONS/SIGNIFICANCE: S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins. These findings are consistent with models for receptor activation in which ligand-binding or T-ALL-associated mutations lead to conformational changes of the NRR that permit metalloprotease cleavage.en_US
dc.description.sponsorshipP01 119070 - PHS HHS; P01 CA119070 - NCI NIH HHS; P01 CA119070-030003 - NCI NIH HHS; R01 CA092433-05S1 - NCI NIH HHS; P01 CA119070-01A10003 - NCI NIH HHS; R01 CA092433 - NCI NIH HHS; P01 CA119070-039001 - NCI NIH HHS; P01 CA119070-029001 - NCI NIH HHS; P01 CA119070-020003 - NCI NIH HHS; R01 CA092433-05 - NCI NIH HHS; R01 CA092433-04 - NCI NIH HHS; P01 CA119070-01A19001 - NCI NIH HHS; R01 CA092433-06A2 - NCI NIH HHSen_US
dc.format.extent12 p.en_US
dc.languageEnglish
dc.language.isoen_US
dc.publisherPUBLIC LIBRARY SCIENCEen_US
dc.relation.ispartofPLOS ONE
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 Internationalen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subjectScience & technologyen_US
dc.subjectMultidisciplinary sciencesen_US
dc.subjectAmino acid sequenceen_US
dc.subjectDimerizationen_US
dc.subjectFurinen_US
dc.subjectHumansen_US
dc.subjectHydrolysisen_US
dc.subjectModels, molecularen_US
dc.subjectMolecular sequence dataen_US
dc.subjectMutationen_US
dc.subjectNuclear magnetic resonance, biomolecularen_US
dc.subjectProtein conformationen_US
dc.subjectReceptor, Notch1en_US
dc.subjectReceptor, Notch2en_US
dc.subjectSequence homology, amino aciden_US
dc.subjectSignal transductionen_US
dc.subjectX-ray diffractionen_US
dc.subjectMD multidisciplinaryen_US
dc.subjectGeneral science & technologyen_US
dc.titleEffects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2en_US
dc.typeArticleen_US
dc.description.versionPublished versionen_US
dc.identifier.doi10.1371/journal.pone.0006613
pubs.elements-sourceweb-of-scienceen_US
pubs.notesEmbargo: Not knownen_US
pubs.organisational-groupBoston Universityen_US
pubs.organisational-groupBoston University, College of Arts & Sciencesen_US
pubs.organisational-groupBoston University, College of Arts & Sciences, Department of Chemistryen_US
pubs.publication-statusPublisheden_US
dc.identifier.mycv79935


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