The Japan Academy

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Vol. 85 No. 1 (2009)

Vol. 85 No. 1 (2009)

The structure and subunits of the 26S proteasome consisting of the 20S proteasome (the 20S core particle) and the 19S regulatory particle

  The 26S proteasome (left panel, its averaged image based on electron micrographs) is made up of two subcomplexes, the 20S core complex (CP) and the 19S regulatory particle (RP). Much attention is now focused on the structure and functions of the 26S proteasome because it functions as a protein-destruction machine in ubiquitin-dependent proteolysis, which plays essential roles in almost all cellular events such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein quality control and development.The 20S CP (also known as the 20S proteasome) is classified as a threonine protease that contains two pairs of three different catalytic sites (see the left panel, the two scissors shown in yellow). The middle panel shows its overall tertiary structure, whereas the structures of the terminal 19S RP have not yet been determined and are depicted by question marks. The 26S proteasome consists of many different subunits (right panel). The central 20S CP forms an α1-7β1-7β1-7α1-7 structure with axial stacking of two outer α and two inner β rings, which are made up of seven similar α and β subunits, respectively: β1, β2, and β5 contain catalytic sites with caspase-like, trypsin-like, and chymotrypsin-like activities, respectively. The 19S RP comprises approximately 20 different subunits that can be classified into Rpt and Rpn ones and comprises two subcomplexes, the lid and the base: The former subcomplex is composed of at least nine Rpn subunits (Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, Rpn12 and Rpn15), while the latter is composed of six Rpt (Rpt1-Rpt6) and four Rpn (Rpn1, Rpn2, Rpn10 and Rpn13) subunits. Rpn10 and Rpn13 function as ubiquitin receptors that trap polyubiquityalted proteins, Rpn11 functions as a metalloprotease that cleaves the polyubiquitin chains tagged to client proteins at a proximal site and a hexameric ring containing Rpt1-Rpt6 promotes unfolding of client proteins and the gate opening of the 20S CP. There are several subtypes of the vertebrate proteasomes: The immunoproteasome and the thymoproteasome, which have different subunit structures and substrate specificities from those of the standard (or constitutive) proteasome, play important roles in antigen processing and positive selection of developing thymocytes, respectively. In addition, various proteasome inhibitors have been developed and one of the inhibitors has recently been approved for the treatment of multiple myeloma.

Hideyoshi Yokosawa
RIKEN Brain Research Institute