Seminar

Sorting It All Out: Signal-mediated Protein Traffic in the Endosomal-Lysosomal System

Juan S Bonifacino, PhD

Sorting of transmembrane proteins to endosomes, lysosomes, lysosome-related organelles and the basolateral plasma membrane of polarized epithelial cells is mediated by signals present in the cytosolic domains of the proteins. Most signals consist of short, linear arrays of amino acids that conform to canonical sequence motifs, the best characterized of which are known as "tyrosine-based" and "dileucine-based" signals. These signals are recognized by adaptor proteins that are components of proteins coats. Four adaptor protein (AP) complexes named AP-1, AP-2, A-3 and AP-4, have been shown to play key roles in signal recognition. Of these, AP-4 is the most recently discovered and least well-characterized. We recently found that the mu4 subunit of AP-4 interacts with an YKFFE sequence from the cytosolic tail of the Alzheimer’s Disease (AD) amyloid precursor protein (APP). Biochemical and X-ray crystallographic analyses showed that the sequence requirements and binding site for this interaction are distinct from those of other signal-adaptor interactions. Disruption of the AP-4-APP interaction was found to redistribute APP from endosomes to the trans-Golgi network (TGN), and to enhance gamma-secretase-catalyzed cleavage of APP to the pathogenic amyloid-beta peptide. These findings demonstrate that APP and AP-4 engage in a novel type of signal-adaptor interaction that mediates transport of APP from the TGN to endosomes, thus reducing amyloidogenic processing of the protein.