RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association

Goodman, K.M. and Kjær, S. and Beuron, F. and Knowles, P.P. and Nawrotek, A. and Burns, E.M. and Purkiss, A.G. and George, R. and Santoro, M. and Morris, E.P. and McDonald, Neil Q. (2014) RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. Cell Reports 18 (6), pp. 1894-1904. ISSN 2211-1247.

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 (RETECD), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RETECD 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 RETECD 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.

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