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, K KFF. However, overexpressed ERGIC-53 is transported to the cell surfac e and rapidly endocytosed. Here we report that ERGIC-53 carries a prev iously undescribed endocytosis signal, Surprisingly, the signal was KK FF and like the ER-retrieval signal required a C-terminal position. In fact, the minimal consensus sequence determined by substitutional mut agenesis (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 consen sus sequence, The relatedness of the two signals suggests that coatome r-mediated retrieval of proteins may be mechanistically more related t o clathrin-dependent sorting than previously anticipated.