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Publication Abstract from PubMed

RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRalpha 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 RET(ECD)-GDNF-GFRalpha1a 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 GFRalpha co-receptors, while its rigid arm recognizes a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualize linear arrays of RET(ECD)-GDNF-GFRalpha1a 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.

A two-site flexible clamp mechanism for RET-GDNF-GFRalpha1 assembly reveals both conformational adaptation and strict geometric spacing.,Adams SE, Purkiss AG, Knowles PP, Nans A, Briggs DC, Borg A, Earl CP, Goodman KM, Nawrotek A, Borg AJ, McIntosh PB, Houghton FM, Kjaer S, McDonald NQ Structure. 2021 Jan 11. pii: S0969-2126(20)30479-2. doi:, 10.1016/j.str.2020.12.012. PMID:33484636^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.