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UNC119 is required for G protein trafficking in sensory neurons
Houbin Zhang1,10, Ryan Constantine1,2,10, Sergey Vorobiev3, Yang Chen3, Jayaraman Seetharaman3, Yuanpeng Janet Huang4, Rong Xiao4, Gaetano T Montelione4, Cecilia D Gerstner1, M Wayne Davis5,George Inana6, Frank G Whitby7, Erik M Jorgensen5,8, Christopher P Hill7, Liang Tong3 & Wolfgang Baehr1,5,9
UNC119 is widely expressed among vertebrates and other phyla. We found that UNC119 recognized the acylated N terminus of the rod photoreceptor transducin a (Ta) subunit and Caenorhabditis elegans G proteins ODR-3 and GPA-13. The crystal structure of human UNC119 at 1.95- resolution revealed an immunoglobulin-like b-sandwich fold. Pulldowns and isothermal titration calorimetry revealed a tight interaction between UNC119 and acylated Ga peptides. The structure of co-crystalsof UNC119 with an acylated Ta N-terminal peptide at 2.0 revealed that the lipid chain is buried deeply into UNC119s hydrophobic cavity. UNC119 bound Ta-GTP, inhibiting its GTPase activity, thereby providing a stable UNC119Ta-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.
2011Nature America, Inc. All rights reserved.
2011Nature America, Inc. All rights reserved.
Non-motile primary cilia sensitive to external stimuli are found in various animal sensory neurons. In mammalian photoreceptors or C. elegans olfactory cells, light receptors (rhodopsin) or odorant receptors, together with their G proteins and associated signal transduction components, are transported to cilia by vesicular and intraflagellar mechanisms. Defects in these trafficking pathways have been shown to impair signal transduction, ciliogenesis and cilia maintenance1, often leading to severe disease. For both photoreceptors and odorant receptors, evidence continues to emerge of an ever-increasing number of polypeptides involved in vesicular trafficking and stabilizing intraflagellar transport, including components of the BBSome2, Rab GTPases3, Arf and Arf-like GTPases4 and prenyl-binding proteins5.
UNC119 is a 27-kDa polypeptide identified in the basal body proteome of C. reinhardtii6, the flagellar rootlet of Naegleria gruberi7, neurons of C. elegans8 and the mouse photoreceptor sensory cilium complex9. unc-119 was first discovered in C. elegans on the basis of a spontaneous mutation affecting locomotion, feeding behavior and chemosensation8. Independently, a protein named retina...