Studies in this group have focused on the cellular and molecular mechanisms that determine the intracellular fate of newly synthesized proteins within the secretory pathway. Areas of interest have included the relationship between protein structure and fate of proteins in the endoplasmic reticulum (ER), and the mechanism of protein localization to the trans-Golgi network (TGN). During this period, we have investigated the cause for the intracellular retention of glycosylphosphatidylinositol (GPI)-anchored proteins in cells deficient in the synthesis of GPI. This metabolic defect is thought to be the cause of the human disorder, paroxysmal nocturnal hemoglobinuria (PNH). Our studies have shown that precursors of GPI- anchored proteins are retained and degraded within the ER of GPI- deficient cells, and that the ER retention/degradation phenotype is due to the presence of an uncleaved signal for GPI-anchor addition. GPI- anchoring signals show a remarkable resemblance to the """"""""heterophilic sequence"""""""" motif previously shown in our laboratory to mediate assembly and ER retention/degradation of unassembled subunits of the T-cell antigen receptor. We have also investigated the assembly of class II MHC molecules in the ER. Our studies have led to the discovery of a role for transmembrane (TM) domain interactions in the assembly of class II MHC molecules. TM domain interactions are required for correct assembly and efficient intracellular transport of newly synthesized molecules, and are mediated by a novel structural motif involving several glycine residues on the same face of a transmembrane alpha-helix. A signal for protein localization to the TGN has been identified within the cytoplasmic tail of the integral membrane glycoprotein, TGN38. The TGN localization signal is related to endocytosis signals, and may mediate binding to receptor-like molecules. Other proteins localized to the TGN have been found to have similar structural motifs, suggesting the existence of a general mechanism for TGN localization in eukaryotic cells.
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