dc.contributor.author | Goodman, KM | |
dc.contributor.author | Kjær, S | |
dc.contributor.author | Beuron, F | |
dc.contributor.author | Knowles, PP | |
dc.contributor.author | Nawrotek, A | |
dc.contributor.author | Burns, EM | |
dc.contributor.author | Purkiss, AG | |
dc.contributor.author | George, R | |
dc.contributor.author | Santoro, M | |
dc.contributor.author | Morris, EP | |
dc.contributor.author | McDonald, NQ | |
dc.date.accessioned | 2020-08-13T11:44:02Z | |
dc.date.issued | 2014-09-25 | |
dc.identifier.citation | Cell reports, 2014, 8 (6), pp. 1894 - 1904 | |
dc.identifier.issn | 2211-1247 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3949 | |
dc.identifier.eissn | 2211-1247 | |
dc.identifier.doi | 10.1016/j.celrep.2014.08.040 | |
dc.description.abstract | The 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.format | Print-Electronic | |
dc.format.extent | 1894 - 1904 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | CELL PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | CHO Cells | |
dc.subject | Cell Membrane | |
dc.subject | Animals | |
dc.subject | Zebrafish | |
dc.subject | Humans | |
dc.subject | Cricetulus | |
dc.subject | Rats | |
dc.subject | Zebrafish Proteins | |
dc.subject | Recombinant Proteins | |
dc.subject | Antibodies | |
dc.subject | Epitopes | |
dc.subject | Sequence Alignment | |
dc.subject | Binding Sites | |
dc.subject | Amino Acid Sequence | |
dc.subject | Protein Structure, Tertiary | |
dc.subject | Protein Binding | |
dc.subject | Molecular Sequence Data | |
dc.subject | Cricetinae | |
dc.subject | Proto-Oncogene Proteins c-ret | |
dc.subject | Glial Cell Line-Derived Neurotrophic Factor Receptors | |
dc.subject | Glial Cell Line-Derived Neurotrophic Factor | |
dc.title | RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2014-08-17 | |
rioxxterms.versionofrecord | 10.1016/j.celrep.2014.08.040 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2014-09-18 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cell reports | |
pubs.issue | 6 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 8 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Structural Electron Microscopy | |
dc.contributor.icrauthor | Beuron, Fabienne | |
dc.contributor.icrauthor | Morris, Edward | |