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dc.contributor.authorXiong, S
dc.contributor.authorLorenzen, K
dc.contributor.authorCouzens, AL
dc.contributor.authorTempleton, CM
dc.contributor.authorRajendran, D
dc.contributor.authorMao, DYL
dc.contributor.authorJuang, Y-C
dc.contributor.authorChiovitti, D
dc.contributor.authorKurinov, I
dc.contributor.authorGuettler, S
dc.contributor.authorGingras, A-C
dc.contributor.authorSicheri, F
dc.date.accessioned2018-06-08T08:07:09Z
dc.date.issued2018-08-07
dc.identifier.citationStructure (London, England : 1993), 2018, 26 (8), pp. 1101 - 1115.e6
dc.identifier.issn0969-2126
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1755
dc.identifier.eissn1878-4186
dc.identifier.doi10.1016/j.str.2018.05.014
dc.description.abstractThe human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase domain in its non-phosphorylated state, revealing a fully resolved atypically long activation segment that blocks substrate binding and stabilizes a non-productive position of helix αC. Consistent with an auto-inhibitory function, mutations within the activation segment of NDR1 dramatically enhance in vitro kinase activity. Interestingly, NDR1 catalytic activity is further potentiated by MOB1 binding, suggesting that regulation through modulation of the activation segment and by MOB1 binding are mechanistically distinct. Lastly, deleting the auto-inhibitory activation segment of NDR1 causes a marked increase in the association with upstream Hippo pathway components and the Furry scaffold. These findings provide a point of departure for future efforts to explore the cellular functions and the mechanism of NDR1.
dc.formatPrint-Electronic
dc.format.extent1101 - 1115.e6
dc.languageeng
dc.language.isoeng
dc.publisherCELL PRESS
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectEpithelial Cells
dc.subjectHumans
dc.subjectEscherichia coli
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectHepatocyte Growth Factor
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectMicrotubule-Associated Proteins
dc.subjectProto-Oncogene Proteins
dc.subjectRecombinant Proteins
dc.subjectCrystallography, X-Ray
dc.subjectCloning, Molecular
dc.subjectSequence Alignment
dc.subjectSignal Transduction
dc.subjectGene Expression
dc.subjectGene Expression Regulation
dc.subjectBinding Sites
dc.subjectAmino Acid Sequence
dc.subjectProtein Binding
dc.subjectSequence Homology, Amino Acid
dc.subjectSubstrate Specificity
dc.subjectKinetics
dc.subjectMutation
dc.subjectGenetic Vectors
dc.subjectModels, Molecular
dc.subjectProtein Interaction Domains and Motifs
dc.subjectHEK293 Cells
dc.subjectProtein Conformation, alpha-Helical
dc.subjectProtein Conformation, beta-Strand
dc.titleStructural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.
dc.typeJournal Article
dcterms.dateAccepted2018-05-17
rioxxterms.versionofrecord10.1016/j.str.2018.05.014
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
rioxxterms.licenseref.startdate2018-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfStructure (London, England : 1993)
pubs.issue8
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Biology of Cell Signalling
pubs.publication-statusPublished
pubs.volume26
pubs.embargo.termsNot known
icr.researchteamStructural Biology of Cell Signalling
dc.contributor.icrauthorGuettler, Sebastian


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