title: Regulated intramembrane proteolysis--lessons from amyloid precursor protein processing.
abstract: Regulated intramembrane proteolysis (RIP) controls the communication between cells and the extracellular environment. RIP is essential in the nervous system, but also in other tissues. In the RIP process, a membrane protein typically undergoes two consecutive cleavages. The first one results in the shedding of its ectodomain. The second one occurs within its transmembrane domain, resulting in secretion of a small peptide and the release of the intracellular domain into the cytosol. The proteolytic cleavage fragments act as versatile signaling molecules or are further degraded. An increasing number of membrane proteins undergo RIP. These include growth factors, cytokines, cell adhesion proteins, receptors, viral proteins and signal peptides. A dysregulation of RIP is found in diseases, such as leukemia and Alzheimer's disease. One of the first RIP substrates discovered was the amyloid precursor protein (APP). RIP processing of APP controls the generation of the amyloid β-peptide, which is believed to cause Alzheimer's disease. Focusing on APP as the best-studied RIP substrate, this review describes the function and mechanism of the APP RIP proteases with the goal to elucidate cellular mechanisms and common principles of the RIP process in general.
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases, Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000502:physiology*; D013379:Substrate Specificity
chemical_list: D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins