This group investigates the molecular mechanisms that determine the intracellular localization and sorting of integral membrane proteins in the endocytic and secretory pathways. This past year, our efforts have been primarily directed towards identifying and characterizing proteins that recognize cytoplasmic sorting signals. We had previously demonstrated that tyrosine-based sorting signals that mediate internalization from the cell surface and lysosomal targeting interacted specifically with the medium chains, mu1 and mu2, of the clathrin-associated adaptor complexes, AP-1 and AP-2. We have now conducted a detailed characterization of the factors that determine the specificity and the avidity of the signal-adaptor interactions. The requirements for interaction gleaned from these studies provide a mechanistic explanation for the involvement of tyrosine-based signals in various sorting processes. During the past year, we have also described the existence of a novel, ubiquitously-expressed adaptor-like complex that is, at least partially, associated with endosomes. This complex also recognizes tyrosine-based sorting signals and may be involved in sorting proteins for transport between early and late endosomes. Finally, we have collaborated with Allan Weissman (NCI) to identify the determinants of localization of the protein UBC6 to the endoplasmic reticulum (ER). The results of this study indicate that information leading to ER localization of UBC6 is contained within the membrane anchor of the protein and that the mechanism of localization may involve partitioning into membranes of different lipid composition.
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