RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association.
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ICR Authors
Authors
Goodman, KM
Kjær, S
Beuron, F
Knowles, PP
Nawrotek, A
Burns, EM
Purkiss, AG
George, R
Santoro, M
Morris, EP
McDonald, NQ
Kjær, S
Beuron, F
Knowles, PP
Nawrotek, A
Burns, EM
Purkiss, AG
George, R
Santoro, M
Morris, EP
McDonald, NQ
Document Type
Journal Article
Date
2014-09-25
Date Accepted
2014-08-17
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.
Citation
Cell reports, 2014, 8 (6), pp. 1894 - 1904
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
Collections
Research Team
Structural Electron Microscopy