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dc.contributor.authorGoodman, KM
dc.contributor.authorKjær, S
dc.contributor.authorBeuron, F
dc.contributor.authorKnowles, PP
dc.contributor.authorNawrotek, A
dc.contributor.authorBurns, EM
dc.contributor.authorPurkiss, AG
dc.contributor.authorGeorge, R
dc.contributor.authorSantoro, M
dc.contributor.authorMorris, EP
dc.contributor.authorMcDonald, NQ
dc.date.accessioned2020-08-13T11:44:02Z
dc.date.issued2014-09-25
dc.identifier.citationCell reports, 2014, 8 (6), pp. 1894 - 1904
dc.identifier.issn2211-1247
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3949
dc.identifier.eissn2211-1247
dc.identifier.doi10.1016/j.celrep.2014.08.040
dc.description.abstractThe RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RET(ECD)), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RET(ECD) envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RET(ECD) cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation.
dc.formatPrint-Electronic
dc.format.extent1894 - 1904
dc.languageeng
dc.language.isoeng
dc.publisherCELL PRESS
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCHO Cells
dc.subjectCell Membrane
dc.subjectAnimals
dc.subjectZebrafish
dc.subjectHumans
dc.subjectCricetulus
dc.subjectRats
dc.subjectZebrafish Proteins
dc.subjectRecombinant Proteins
dc.subjectAntibodies
dc.subjectEpitopes
dc.subjectSequence Alignment
dc.subjectBinding Sites
dc.subjectAmino Acid Sequence
dc.subjectProtein Structure, Tertiary
dc.subjectProtein Binding
dc.subjectMolecular Sequence Data
dc.subjectCricetinae
dc.subjectProto-Oncogene Proteins c-ret
dc.subjectGlial Cell Line-Derived Neurotrophic Factor Receptors
dc.subjectGlial Cell Line-Derived Neurotrophic Factor
dc.titleRET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association.
dc.typeJournal Article
dcterms.dateAccepted2014-08-17
rioxxterms.versionofrecord10.1016/j.celrep.2014.08.040
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2014-09-18
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCell reports
pubs.issue6
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 Electron Microscopy
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 Electron Microscopy
pubs.publication-statusPublished
pubs.volume8
pubs.embargo.termsNot known
icr.researchteamStructural Electron Microscopy
dc.contributor.icrauthorBeuron, Fabienne
dc.contributor.icrauthorMorris, Edward


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