|ZFIN ID: ZDB-PUB-170214-292|
RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association
Goodman, K.M., Kjær, S., Beuron, F., Knowles, P.P., Nawrotek, A., Burns, E.M., Purkiss, A.G., George, R., Santoro, M., Morris, E.P., McDonald, N.Q.
|Source:||Cell Reports 8: 1894-904 (Journal)|
|Registered Authors:||Santoro, Massimo|
|PubMed:||25242331 Full text @ Cell Rep.|
Goodman, K.M., Kjær, S., Beuron, F., Knowles, P.P., Nawrotek, A., Burns, E.M., Purkiss, A.G., George, R., Santoro, M., Morris, E.P., McDonald, N.Q. (2014) RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. Cell Reports. 8:1894-904.
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.