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Title | RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. |
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Journal, issue, pages | Cell Rep, Vol. 8, Issue 6, Page 1894-1904, Year 2014 |
Publish date | Sep 25, 2014 |
Authors | Kerry M Goodman / Svend Kjær / Fabienne Beuron / Phillip P Knowles / Agata Nawrotek / Emily M Burns / Andrew G Purkiss / Roger George / Massimo Santoro / Edward P Morris / Neil Q McDonald / |
PubMed 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 ...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. |
External links | Cell Rep / PubMed:25242331 |
Methods | EM (single particle) |
Resolution | 24.0 - 26.0 Å |
Structure data | EMDB-2712: Structure of the RET receptor tyrosine kinase extracellular domain EMDB-2713: |
Chemicals | ChemComp-CA: |
Source |
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Keywords | SIGNALING PROTEIN / VERTEBRATE DEVELOPMENT / HUMAN DISEASES / PART OF THE RET-GFL- GFRA COMPLEX |