Figure 6

Divergent GFRα1/GFRAL co-receptor D1 domain positions within the RET^ECD ternary complex

(A) The D1-D2 domain linker motif (SPYE), highlighted in cyan is conserved between zGFRα1a, GFRα1, GFRα2, and GFRα3. It is missing from the shorter GFRα4 that lacks a D1 domain altogether and from the divergent GFRAL.

(B) Schematic diagram of human RET^ECD, GFRAL, and GDF15 construct boundaries used and individual domains annotated as in Figure 1.

(C) (i) Negative stain EM envelope of a reconstituted hRET^ECD_2-hGDF15₂-hGFRAL₂ (hR15AL) complex docked with hR15AL (PDB: 6Q2J) revealing additional map potential indicated by a green Gaussian volume (generated from a D1 domain homology model). (ii) Cryo-EM map of zRGα1a (light gray) superposed with the final model (colored as in Figure 2) with GFRα1a^D1 shown (light green Gaussian volume at 5 Å²).

(D) Comparison of co-receptor D1 domain position and interfaces (i) GFRAL^D1 makes different contacts to domains D2-D3 (green), GFRAL^D1 shown as a 30 Å² Gaussian volume (light green), and GDF15 (salmon). (ii) zGFRα1a^D1 contacts and colored as in Figure 2. zGFRα1a^D1 represented as a 5 Å² Gaussian volume (light green).