Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.13.286047v1?rss=1 Authors: Adams, S., Purkiss, A. G., Knowles, P. P., Nans, A., Briggs, D. C., Borg, A., Earl, C. P., Goodman, K. M., Nawrotek, A., Borg, A. J., McIntosh, P. B., Houghton, F. M., Kjaer, S., McDonald, N. Q. Abstract: RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFR co-receptors recognise 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-CLD3. Comparison with a cryo-EM structure of a ligand-engaged zebrafish RETECD-GDNF-GFR1 complex indicates conformational changes within a clade-specific CLD3 loop adjacent to co-receptor. Our observations indicate RET is a molecular clamp with a flexible calcium-dependent arm that adapts to different GFR co-receptors, while its rigid arm recognises a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualise linear arrays of RETECD-GDNF-GFR1 suggesting a conserved contact stabilises higher-order species. Our study reveals ligand-co-receptor recognition by RET involves both receptor plasticity and strict spacing of receptor dimers by GFL ligands. Copy rights belong to original authors. Visit the link for more info