A novel endocytosis signal related to the KKXX ER‐retrieval signal.

Membrane proteins often contain a sorting signal in their cytoplasmic tail that promotes their clustering into coated vesicles at a specific cellular site. ERGIC‐53 contains a cytoplasmic ER‐retrieval signal, KKFF. However, overexpressed ERGIC‐53 is transported to the cell surface and rapidly endocytosed. Here we report that ERGIC‐53 carries a previously undescribed endocytosis signal. Surprisingly, the signal was KKFF and like the ER‐retrieval signal required a C‐terminal position. In fact, the minimal consensus sequence determined by substitutional mutagenesis (K‐K/R‐F/Y‐F/Y) was related to the ER‐retrieval consensus (K‐K‐X‐X). Furthermore, we provide evidence that internalization of VIP36, a protein that cycles between plasma membrane and Golgi, is mediated by a signal at its C‐terminus that matches the internalization consensus sequence. The relatedness of the two signals suggests that coatomer‐mediated retrieval of proteins may be mechanistically more related to clathrin‐dependent sorting than previously anticipated.