7AML

RET/GDNF/GFRa1 extracellular complex Cryo-EM structure

Summary for 7AML

• Entry DOI: 10.2210/pdb7aml/pdb
• Related: 7AB8 7AMK
• EMDB information: 11822
• Descriptor: Proto-oncogene tyrosine-protein kinase receptor Ret, GDNF family receptor alpha, Glial cell line-derived neurotrophic factor, ... (5 entities in total)
• Functional Keywords: vertebrate development, part of the ret-gfl-gfra complex, neurotrophic factor, signaling protein
• Biological source: Danio rerio (Zebrafish); More
• Total number of polymer chains: 6
• Total formula weight: 245538.29

Authors

Adams, S.E.,Earl, C.P.,Purkiss, A.G.,McDonald, N.Q. (deposition date: 2020-10-09, release date: 2021-01-13, Last modification date: 2024-11-13)

Primary citation

Adams, S.E.,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.
A two-site flexible clamp mechanism for RET-GDNF-GFR alpha 1 assembly reveals both conformational adaptation and strict geometric spacing.
Structure, 29:694-, 2021

PubMed 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 RET-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 RET-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.

PubMed: 33484636
DOI: 10.1016/j.str.2020.12.012

Experimental method

ELECTRON MICROSCOPY (3.5 Å)