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dc.contributor.authorCouzens, ALen_US
dc.contributor.authorXiong, Sen_US
dc.contributor.authorKnight, JDRen_US
dc.contributor.authorMao, DYen_US
dc.contributor.authorGuettler, Sen_US
dc.contributor.authorPicaud, Sen_US
dc.contributor.authorKurinov, Ien_US
dc.contributor.authorFilippakopoulos, Pen_US
dc.contributor.authorSicheri, Fen_US
dc.contributor.authorGingras, A-Cen_US
dc.date.accessioned2017-07-13T15:53:18Z
dc.date.issued2017-06en_US
dc.identifier.citationMolecular & cellular proteomics : MCP, 2017, 16 (6), pp. 1098 - 1110en_US
dc.identifier.issn1535-9476en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/701
dc.identifier.eissn1535-9484en_US
dc.identifier.doi10.1074/mcp.m116.065490en_US
dc.description.abstractThe Hippo tumor suppressor pathway regulates organ size and tissue homoeostasis in response to diverse signaling inputs. The core of the pathway consists of a short kinase cascade: MST1 and MST2 phosphorylate and activate LATS1 and LATS2, which in turn phosphorylate and inactivate key transcriptional coactivators, YAP1 and TAZ (gene WWTR1). The MOB1 adapter protein regulates both phosphorylation reactions firstly by concurrently binding to the upstream MST and downstream LATS kinases to enable the trans phosphorylation reaction, and secondly by allosterically activating the catalytic function of LATS1 and LATS2 to directly stimulate phosphorylation of YAP and TAZ. Studies of yeast Mob1 and human MOB1 revealed that the ability to recognize phosphopeptide sequences in their interactors, Nud1 and MST2 respectively, was critical to their roles in regulating the Mitotic Exit Network in yeast and the Hippo pathway in metazoans. However, the underlying rules of phosphopeptide recognition by human MOB1, the implications of binding specificity for Hippo pathway signaling, and the generality of phosphopeptide binding function to other human MOB family members remained elusive.Employing proteomics, peptide arrays and biochemical analyses, we systematically examine the phosphopeptide binding specificity of MOB1 and find it to be highly complementary to the substrate phosphorylation specificity of MST1 and MST2. We demonstrate that autophosphorylation of MST1 and MST2 on several threonine residues provides multiple MOB1 binding sites with varying binding affinities which in turn contribute to a redundancy of MST1-MOB1 protein interactions in cells. The crystal structures of MOB1A in complex with two favored phosphopeptide sites in MST1 allow for a full description of the MOB1A phosphopeptide-binding consensus. Lastly, we show that the phosphopeptide binding properties of MOB1A are conserved in all but one of the seven MOB family members in humans, thus providing a starting point for uncovering their elusive cellular functions.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1098 - 1110en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectHela Cellsen_US
dc.subjectHumansen_US
dc.subjectProtein-Serine-Threonine Kinasesen_US
dc.subjectAdaptor Proteins, Signal Transducingen_US
dc.subjectPhosphopeptidesen_US
dc.subjectRecombinant Proteinsen_US
dc.subjectSignal Transductionen_US
dc.subjectProtein Bindingen_US
dc.subjectPhosphorylationen_US
dc.titleMOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-04-03en_US
rioxxterms.versionofrecord10.1074/mcp.m116.065490en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2017-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMolecular & cellular proteomics : MCPen_US
pubs.issue6en_US
pubs.notesNo embargoen_US
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-statusPublisheden_US
pubs.volume16en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamStructural Biology of Cell Signallingen_US
dc.contributor.icrauthorGuettler, Sebastianen_US


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