Traffic COPs: rules of detection.

How specific cargo recognition by coat proteins is achieved and how this recognition event may regulate vesicle formation are still under investigation. In two recent papers by the Owen and Goldberg labs, the binding mode of dilysine motifs to the coatomer of the COPI coat has been analysed. Collectively, their findings suggest that the dilysine motif containing cargo proteins may stabilize coat complexes on membranes and enhance the chance for coat polymerization and vesicle budding. The balance of anterograde and retrograde transport between the endoplasmic reticulum (ER) and the Golgi apparatus and within the Golgi is essential for organelle identity and maintenance, and ultimately for cell survival. Communication between organelles along this secretory pathway is maintained by coated transport vesicles. While anterograde transport to the ER is dependent on COPI vesicles, retrograde transport within the Golgi and back to the ER requires COPI action. The main function of COPI vesicles is to retrieve proteins and lipids back to the previous compartment along the pathway. COPI-dependent cargoes display motifs on their cytoplasmic tail that are recognized by the coat complex to allow for their transport. Unfortunately, pathogens—or factors expressed by them—also explore the COPI traffic route to exert their detrimental function on host cells. For example, toxins from shigella and cholera use the COPI transport system to reach the ER, from which they escape to the cytoplasm to fulfill their harmful function. In addition, functional COPI traffic is essential for the replication of a number of viruses, presumably because they transport obligatory factors for replication initiation. Thus, understanding the molecular basis of cargo recognition by the COPI coat is not only exciting for intracellular transport aficionados, but will also guide the rationale to fight pathogens depending on COPI transport for infection. Transmembrane proteins exposing a KKXX or a KXKXX motif on their C-terminal tail have been shown to be COPIdependent cargo molecules that are retrieved from the Golgi apparatus to the ER. These motifs are also found in either ERresident proteins that may escape sometimes or proteins that facilitate export of other cargo from the ER in COPII vesicles, and which serve as some sort of export receptors. Once the cargo-transport receptor complex has reached the Golgi, the complex dissociates and while the cargo moves through the Golgi, the transport receptors are recycled back to the ER through the retrieval sequence. Given the importance of the dilysine-based motifs, researchers mapped the interaction site of the cargo tails with COPI. The COPI coat consists mainly of the small GTPase Arf1 and the heptameric protein complex coatomer (a, b, b0, d, e, g, z). The coatomer complex, although recruited en bloc to membranes, can be subdivided into two subcomplexes: a clathrin adaptor-like complex (b, d, g, z) and an outer shell complex (a, b0, e). In clathrin-dependent trafficking, cargo recognition occurs in the adaptor complex, which is also true for the COPI coat with respect to a di-arginine-based signal recognition motif. However, a number of experiments by different groups demonstrated that the dilysine-based signals are recognized by the outer shell complex (Cosson