AN N-TERMINAL DOUBLE-ARGININE MOTIF MAINTAINS TYPE-II MEMBRANE-PROTEINS IN THE ENDOPLASMIC-RETICULUM

Use of alternative initiator methionines in human invariant (Ii) chain mRNA results in the synthesis of tno polypeptides, Iip33 and Iip31. A fter synthesis both isoforms are inserted into the endoplasmic reticul um (ER) as type II membrane proteins. Subsequently, Iip31 is transport ed out of the ER, guiding MHC class II to the endocytic pathway, where as Iip33, which differs by only a 16 residue extension at the N-termin us, becomes an ER resident. Mutagenesis of thisextension showed that m ultiple arginines close to the N-terminus were responsible for ER targ eting. The minimal requirements of this targeting motif were found to be two arginines (RR) located at positions 2 and 3, 3 and 4 or 4 and 5 or split by a residue at positions 2 and 4 or 3 and 5. Transplanting a n RR moth onto transferrin receptor demonstrated that this motif can t arget other type II membrane proteins to the ER. The characteristics o f this RR moth are similar to the Ill; ER targeting moth for type I me mbrane proteins. Indeed? RR-tagged transferrin receptor partially loca lized to the intermediate compartment, suggesting that Like the KK mot h, the RR motif directs the retrieval of membrane proteins to the ER v ia a retrograde transport pathway.