Extended Data Fig. 2: Schematic representation of predicted domains in putative Nematostella GABA_BR homologs in comparison to human GABA_B1R.

The eight Nematostella proteins contain a conserved signal peptide, an extracellular ‘Periplasmic Binding Protein type1 (PBP1) GABA_B ligand-binding domain’ (the structural VFT module that in mammals binds GABA), predicted helical transmembrane domains, and coiled-coil domains. One Nematostella homolog (v1g206093) contained two extracellular domains, each corresponding to a separate predicted VFT module. These two domains are 26% identical in sequence, suggesting that they serve dissimilar functions (Supplementary Fig. 2). v1g243252 contains eight predicted TM helices and a ~300 residue domain of unknown function (DUF4475) located after these TM domains. However, the intracellular C-terminal domains of the Nematostella homologs present low similarity to the corresponding regions of human sequences. Coiled-coil motifs found in the C-terminus of human GABA_BR were predicted in three Nematostella homologs. The mammalian GABA_BR C-terminal domain mediate processes such as trafficking out of the ER or modulation of receptor activity⁴⁴, but it has also been suggested as non-essential for functional GABA_BR heterodimers^42,43,45. GABA_BR C-termini therefore differ dramatically between mammals and cnidarians, suggesting they do not affect essential functions, and were excluded from the full comparison. Protein domains were predicted as detailed in Methods.