Featured Article - July 2011
Short description: The structure of UNC119 by itself and with a substrate shows how it binds lipids to regulate G protein trafficking.
Sensory neurons—including, but not limited to, olfactory cells and photoreceptors—require proper trafficking of G proteins, sensory receptors and signal transduction components for accurate reporting of environmental stimuli. Many proteins, from GTPases to prenyl-binding proteins, have been implicated to be a part of the transport process. However, the mechanism by which this process is regulated for specific proteins and cell types is not clear.
In Caenorhabditis elegans, loss of the UNC119 protein leads to defects in feeding, chemosensation and locomotion, suggesting that this protein has an important role in the sensory neurons in which it is expressed. Although UNC119 has been seen to bind to a wide variety of targets, how it contributes to sensory neuron signaling has remained elusive. Now, Baehr and colleagues (PSI NESG) have combined X-ray crystallography with functional analysis to show that UNCP119 has an important role in regulating G protein trafficking.
Structural examination of UNC119 revealed that it has a β-sandwich structure similar to that of the prenyl-binding protein PrBP/δ, indicating a potentially similar mechanism of action. Indeed, functional studies indicated that UNC119 interacts with the GTP-bound form of transducin α subunit (Tα), but not other transducin subunits or even GDP-bound Tα associated with Tβγ, in a manner dependent on acylation of the Tα N terminus. The cocrystal structure of UNC119 with a lauroylated Tα peptide shows that the lauroyl group and six residues of Tα are inserted into the hydrophobic pocket of UNC119, revealing why UNC119 binds only acylated Tα.
In the retina, transducin rapidly diffuses from the outer to the inner segment in response to bright light before being slowly shuttled back to the outer segment, but in Unc119 −/− mice the return shuttling of Tα was significantly delayed. Additionally, in unc-119 mutant worms, the acylated sensory neuron protein ODR-3 was not correctly localized, indicating a conserved mechanism of function for UNC119 between species. Combining this functional data with the structural data allowed the authors to put forth a model for UNC119 in regulating the trafficking of G proteins via its lipid-binding properties. The authors propose that the combined mouse and worm data here will provide valuable insights for understanding the regulation of sensory neuron proteins in other species as well.
H. Zhang, R. Constantine et al. UNC119 is required for G protein trafficking in sensory neurons.
Nat. Neurosci (5 June 2011). doi:10.1038/nn.2835