UNC119 is required for G protein trafficking in sensory neurons

UNC119 is widely expressed among vertebrates and other phyla. We found that UNC119 recognized the acylated N terminus of the rod photoreceptor transducin alpha (T alpha) subunit and Caenorhabditis elegans G proteins ODR-3 and GPA-13. The crystal structure of human UNC119 at 1.95-angstrom resolution revealed an immunoglobulin-like beta-sandwich fold. Pulldowns and isothermal titration calorimetry revealed a tight interaction between UNC119 and acylated G alpha peptides. The structure of co-crystals of UNC119 with an acylated T alpha N-terminal peptide at 2.0 angstrom revealed that the lipid chain is buried deeply into UNC119's hydrophobic cavity. UNC119 bound T alpha-GTP, inhibiting its GTPase activity, thereby providing a stable UNC119-T alpha-GTP complex capable of diffusing from the inner segment back to the outer segment after light-induced translocation. UNC119 deletion in both mouse and C. elegans led to G protein mislocalization. Thus, UNC119 is a Ga subunit cofactor essential for G protein trafficking in sensory cilia.