Baker et al. report that photoreceptor proteins lacking targeting sequences end up in the right place thanks to their more abundant, and more goal-oriented, fellow travelers.
Rod and cone cells are divided into four compartments: a synaptic terminal, a nuclear region, an inner segment for protein and lipid synthesis, and an outer segment that contains a highly folded membrane packed with proteins such as light-sensitive rhodopsin. Rhodopsin and some other outer-segment proteins contain targeting signals directing them there, but most outer-segment proteins do not.
To understand how these signal-lacking proteins reach their destination, the authors examined the trafficking of two proteins: R9AP, which is almost exclusively found in the outer segment, and the structurally similar syntaxin 3, localized to the inner segment. Switching the transmembrane domains of the two had no effect on their final destinations, and neither did whittling away at R9AP's cytoplasmic domain. Removing the cytoplasmic domain of syntaxin-3, on the other hand, led the protein to accumulate in the outer segment, whereas adding this domain to R9AP led the protein to accumulate in the inner segment. Syntaxin's cytoplasmic domain thus specifically targets proteins to the inner segment, and without it proteins head to the outer segment by default. The case for the outer segment as the default destination was clinched by removing signal sequences from multiple proteins, all of which then ended up in the outer segment.
R9AP and other signal-lacking proteins might be randomly packaged into vesicles bound for all destinations, but since rhodopsin-bearing vesicles headed for the outer segment are so abundant, “directionless” proteins will wind up where they belong just by going with the crowd.