title: The proteasome: from basic mechanisms to emerging roles.
abstract: The proteasome is a sophisticated, 2.5-MDa, multisubunit complex that contains a catalytic core particle (CP) and two terminal regulatory particles (RPs); the RPs associate with the termini of the central CP at opposite orientations. The CP consists of four axially stacked heptameric rings (two outer α-rings and two inner β-rings), which are made up of seven structurally related, but not identical, α and β subunits. The CP contains catalytic threonine residues (in β1, β2, and β5 with caspase-like, trypsin-like, and chymotrypsin-like activities, respectively) on the surface of the chamber formed by two abutting β-rings. The RP recognizes polyubiquitylated substrate proteins and unfolds and translocates these proteins to the interior of the CP for degradation. The RP comprises 19 different subunits, which are thought to form two subcomplexes called the lid and the base. One longstanding question is how the complex structure of the proteasome is organized with high fidelity. Recently, we proposed a novel assembly mechanism that is assisted by multiple proteasome-dedicated chaperones. In addition, we discovered two immuno-type proteasomes, the immunoproteasome and the thymoproteasome, whose catalytic subunits are replaced by homologous counterparts. These two isoforms perform specialized functions that help discriminate self from non-self in cell-mediated immunity (i.e., they function as enzymes that process intracellular antigens for cytotoxic T lymphocyte responses and thymic positive selection). Moreover, emerging evidence suggests that the proteasome is crucially involved in the pathophysiology of various intractable diseases that are increasing in today's aging society.
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. tanaka-kj@igakuken.or.jp
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000941:Antigens / Q000235:genetics / Q000276:immunology; D020134:Catalytic Domain; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000235:genetics / Q000276:immunology*; D009097:Multienzyme Complexes / Q000235:genetics / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000145:classification / Q000235:genetics / Q000276:immunology*; D021381:Protein Transport; D059748:Proteolysis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
chemical_list: D000941:Antigens; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex