Protein Trafficking

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 Protein Trafficking Background

Endosomal protein trafficking

Endocytosis is the process used by eukaryotic cells to internalize portions of the plasma membrane, containing ligand-bound receptors and other proteins, in the form of a vesicle. The cargo within the vesicle is then delivered to a membrane-bound organelle known as early endosomes. Two mechanisms for endocytosis have been described based on the presence and requirement of the scaffolding protein, clathrin. Clathrin-mediated protein trafficking is the best characterized type of internalization. At the plasma membrane, this process involves the interaction of a receptor intracellular domain with an adaptor protein (i.e. AP-2) that in turn associates with clathrin, forming what is known as a clathrin-coated vesicle (or clathrin-coated vesicle pit). This vesicle is pinched-off the plasma membrane by the protein dynamin, transported by motor proteins and then docked and fused to an aceptor membrane by the action of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. Non-clathrin-mediated protein trafficking is not well understood and in some cases requires the presence of certain microdomains at the plasma membrane known as lipid rafts.

Regardless of the type of endocytosis used by the cell for protein trafficking, vesicles are transported to early endosomes. In a scenario where signal attenuation at the plasma membrane is needed, a ligandbound receptor is transported to the late endosome and multivesicular body and finally reaches the lysosome, where it gets degraded. If along this route the receptor is needed again, then from the early endosome gets recycled back to the plasma membrane. Early and late endosomes, multivesicular bodies and lysosomes can be identified in a cell based on their difference in protein composition and, in the case of lysosomes, their acidic luminal pH. Of particular importance is the role of molecular switches belonging to the large family of small GTPases known as Rabs. When active these proteins “label” the membrane of organelles to coordinate the events involved in the docking and fusion of vesicles. The endosomal protein trafficking results in a highly complex, intertwined network, owing to the constellation of proteins involved at each step. Many of the trafficking routes and machineries are starting to be elucidated.

Recent evidence suggests that endosomal protein trafficking plays a more central role in cell signaling than previously anticipated. The canonical view of the relationship between signaling and endosomal protein trafficking is by signal attenuation of receptors sent to the lysosome for degradation. Interestingly, it has been shown that, at least for EGFR, signaling can propagate even after internalization from a compartment termed as the “signaling endosome”. Thus, not only the endosomal-lysosomal system serves as avenue for trafficking it can also be view as a signaling platform. Mutations in genes encoding endocytic proteins have been identified in human cancer. Similar findings have been made, in the fruit fly Drosophila melanogaster, where mutations in endocytic genes (termed as endocytic tumor suppressors) resulted in tissue growth abnormalities and adult lethality.

The membrane proteins delivered to the early endosome can be grouped into two broad classes: proteins which recycle immediately to the plasma membrane and proteins that travel further into the endocytic pathway. In order to ensure appropriate protein trafficking, these two classes of proteins must be distinguished and routed to the correct compartments. Sorting at the level of the early endosome is accomplished through the recognition of cytosolic amino acid sequences which mediate the retention of a protein within the endosomal system. MPRs and LAMPs present such an endosomal retention sequence and remain in the sorting endosome. Integral membrane proteins lacking these signals (recycling receptors such as the transferrin, asialoglycoprotein and LDL receptors) follow a constitutive pathway from the sorting endosome to the recycling endosome and finally to the cell surface.