Adaptor protein 2-mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing. 2012

Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

The β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER-Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.

UI MeSH Term Description Entries
D008856 Microscopy, Fluorescence Microscopy of specimens stained with fluorescent dye (usually fluorescein isothiocyanate) or of naturally fluorescent materials, which emit light when exposed to ultraviolet or blue light. Immunofluorescence microscopy utilizes antibodies that are labeled with fluorescent dye. Fluorescence Microscopy,Immunofluorescence Microscopy,Microscopy, Immunofluorescence,Fluorescence Microscopies,Immunofluorescence Microscopies,Microscopies, Fluorescence,Microscopies, Immunofluorescence
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D011500 Protein Synthesis Inhibitors Compounds which inhibit the synthesis of proteins. They are usually ANTI-BACTERIAL AGENTS or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins. Protein Synthesis Antagonist,Protein Synthesis Antagonists,Protein Synthesis Inhibitor,Antagonist, Protein Synthesis,Antagonists, Protein Synthesis,Inhibitor, Protein Synthesis,Inhibitors, Protein Synthesis,Synthesis Antagonist, Protein,Synthesis Inhibitor, Protein
D011992 Endosomes Cytoplasmic vesicles formed when COATED VESICLES shed their CLATHRIN coat. Endosomes internalize macromolecules bound by receptors on the cell surface. Receptosomes,Endosome,Receptosome
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D002966 Clathrin The main structural coat protein of COATED VESICLES which play a key role in the intracellular transport between membranous organelles. Each molecule of clathrin consists of three light chains (CLATHRIN LIGHT CHAINS) and three heavy chains (CLATHRIN HEAVY CHAINS) that form a structure called a triskelion. Clathrin also interacts with cytoskeletal proteins.
D004705 Endocytosis Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. ENDOSOMES play a central role in endocytosis. Endocytoses
D004721 Endoplasmic Reticulum A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed) Ergastoplasm,Reticulum, Endoplasmic
D006056 Golgi Apparatus A stack of flattened vesicles that functions in posttranslational processing and sorting of proteins, receiving them from the rough ENDOPLASMIC RETICULUM and directing them to secretory vesicles, LYSOSOMES, or the CELL MEMBRANE. The movement of proteins takes place by transfer vesicles that bud off from the rough endoplasmic reticulum or Golgi apparatus and fuse with the Golgi, lysosomes or cell membrane. (From Glick, Glossary of Biochemistry and Molecular Biology, 1990) Golgi Complex,Apparatus, Golgi,Complex, Golgi

Related Publications

Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
October 2003, The Journal of cell biology,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
February 2022, Journal of cellular and molecular medicine,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
September 2011, IUBMB life,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
October 2008, The Journal of biological chemistry,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
March 2016, Cell reports,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
July 2011, The Journal of biological chemistry,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
April 1998, The Journal of biological chemistry,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
January 2005, The Biochemical journal,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
January 2004, Molecular and cellular biology,
Yogikala Prabhu, and Patricia V Burgos, and Christina Schindler, and Ginny G Farías, and Javier G Magadán, and Juan S Bonifacino
November 2012, The Journal of neuroscience : the official journal of the Society for Neuroscience,
Copied contents to your clipboard!