Targeting of protein ERGIC-53 to the ER/ERGIC/cis-Golgi recycling pathway

In summary our data suggest a model for ERGIC-53 targeting that is based on an active di-lysine ER-retrieval signal that acts together with the COOH-terminal phenylalanines, the RSQQE determinant and the lumenal domain to allow a post-ER localization. Localization of ERGIC-53 in the ER/ERGIC/cis-Golgi system is a result of retrieval and retention. In line with the most recent suggestion that COP's may not be involved in anterograde transport but in selective retrieval of di-lysine-signal-bearing proteins (Letourneur et al., 1994; Pelham, 1994) it is conceivable that KKFF is a retrieval signal whose binding to COPs is weak due to the presence of two COOH-terminal phenylalanines. Reduced COP binding may result in less efficient retrieval that in turn would shift the overall distribution from ER to ERGIC. In contrast, RSQQE together with the lumenal domain may function as a retention signal leading to the known concentration of protein ERGIC-53 in the ERGIC. Subcellular fractionation and COP binding studies will be required to test the role of the individual targeting determinants.