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A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing

DOI: 10.1016/j.str.2020.12.012 DOI Help

Authors: Sarah E. Adams (The Francis Crick Institute (Midland Road)) , Andrew G. Purkiss (Cancer Research UK London Research Institute) , Phillip P. Knowles (Francis Crick Institute) , Andrea Nans (Francis Crick Institute) , David C. Briggs (Francis Crick Institute) , Annabel Borg (Francis Crick Institute) , Christopher P. Earl (Francis Crick Institute) , Kerry Goodman (Francis Crick Institute) , Agata Nawrotek (Francis Crick Institute) , Aaron J. Borg (Francis Crick Institute) , Pauline B. Mcintosh (Francis Crick Institute) , Francesca M. Houghton (Francis Crick Institute) , Svend Kjær (Francis Crick Institute) , Neil Mcdonald (Francis Crick Institute; Birkbeck College, London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 15

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 13775

Open Access Open Access

Abstract: RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET stimulating its cytoplasmic kinase function. The principles for RET ligand-co-receptor recognition are incompletely understood. Here, we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish RET revealing interdomain flexibility between CLD2 and CLD3. Comparison with a cryo-electron microscopy structure of a ligand-engaged zebrafish RETECD-GDNF-GFRα1a complex indicates conformational changes within a clade-specific CLD3 loop adjacent to the co-receptor. Our observations indicate that RET is a molecular clamp with a flexible calcium-dependent arm that adapts to different GFRα co-receptors, while its rigid arm recognizes a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualize linear arrays of RETECD-GDNF-GFRα1a suggesting that a conserved contact stabilizes higher-order species. Our study reveals that ligand-co-receptor recognition by RET involves both receptor plasticity and strict spacing of receptor dimers by GFL ligands.

Journal Keywords: ligand recognition; receptor tyrosine kinase; GDNF family ligands; cryo-EM; X-ray crystallography; glycosylation; cystine knot; RET; co-receptor

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 26/01/2021 09:57


Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)