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SNARE proteins mediate specific membrane fusion events in eukaryotic cells. Ykt6 is a conserved SNARE protein that lacks a protemaceous transmembrane domain, but is both farnesylated and palmitoylated at its C-terminus. While yeast Ykt6p is an essential protein that is suggested to function in multiple biosynthetic transport pathways including ER-Golgi, intra-Golgi, and Golgi-vacuole transports that are important to all cells, mammalian ykt6 protein is predominantly expressed in neurons and the functions do not appear to mirror those of yeast Ykt6p. Despite its C-terminal lipidation, about 60% of ykt6 is soluble in the cytosol as monomers, while the other 40% is found in a pellet fraction and forms unidentified protein complexes. Because of the lipid modifications, particulate ykt6 behaves as an integral membrane protein, thereby suggesting that the C-terminal lipids are stably inserted to the membrane. In neuronal cells, ykt6 localizes to punctate structures that do not overlap with conventional organelle markers, but partially colocalize with sedlin, the protein responsible for the X-linked genetic disease spondyloepiphyseal dysplasia tarda. The N-terminal longin domain of ykt6 not only provides targeting information and a mode of membrane association, but it also functions as an intramolecular lipid chaperone that directly binds to the lipids of its own C-terminus. While the overall tertiary structure of the longin domain is important for the specific targeting to the vesicular structures and the initial membrane association, the lipid chaperone property was encoded in the conserved surface residues. The C-terminal lipids contribute to a stable membrane anchorage of ykt6 and, under certain conditions, can provide spurious dominant mistargeting signals that drive ykt6 to the plasma membrane. Because of the direct interactions between the N-terminal longin domain and the C-terminal lipids, lipidated cytosolic ykt6 is soluble and forms a compact conformation that is recalcitrant to SNARE interactions. Likewise, the longin domain masks the otherwise dominant mistargeting information to localize to the punctate structures of unknown function. Thus, the intramolecular interactions provide a conformational switch to down-regulate the SNARE assembly activity as well as to control the solubility and the subcellular localization of neuronal ykt6.