Figure 1

Rer1p regulates complex assembly in the early secretory pathway. (A) Predicted structure of human Rer1p. Rer1p is composed of 196 amino acids and four transmembrane domains. The amino/carboxyl termini and the loop domains are located in the cytosol. Highlighted are the conserved Y152 residue described for the yeast Sec12p-Rer1p interaction [17] and the di-lysine/di-arginine endoplasmic reticulum (ER) retrieval motif located in the carboxyl terminus [14]. (B) Homology of the ER retrieval motif of Rer1p between various clades and species. The sequence is not identical but the positive charge of the motif is conserved throughout evolution. On the right is indicated the sequence identity of the ortholog proteins compared to human. (C) List of Rer1p interactors identified in yeast and vertebrates so far. (D) Assembly of the γ-secretase complex is superimposed on ER-Golgi trafficking. (i) By competing with anterior pharynx-defective 1 (Aph1) for binding to nicastrin (NCT), Rer1p acts as a limiting factor in the formation of the initial NCT-APH1 subcomplex. Later (ii) presenilin (PSEN) and (iii) PSEN enhancer 2 (PEN2) are incorporated in the complex. Whether PSEN and PEN2 join successively or simultaneously is still controversial. (iv) Rer1p may regulate the integration of PEN2 into the complex. Endoproteolysis of PSEN happens after PEN2 assembly. (v) When the complex is fully assembled, it is trafficked to the Golgi where γ-secretase components are glycosylated. AChR, acetylcholine receptor.