Getting to first base in proteasome assembly

Abstract

Assembly of complex structures such as the eukaryotic 26S proteasome requires intricate mechanisms that ensure precise subunit arrangements. Recent studies have shed light on the pathway for ordered assembly of the base of the 19S regulatory particle of the 26S proteasome by identifying new precursor complexes and four dedicated chaperones involved in its assembly.

Figure 1. Pathways of Proteasome Assembly

The eukaryotic 26S proteasome consists of base, lid, and 20S particles (inset, electron micrographs of structures and subunit composition). The 20S particle is composed of 14 different subunits, and its assembly requires five cofactors (not shown). The proteasome base contains six homologous ATPase subunits (Rpt1–6) that assemble into a hexameric ring with Rpn1 and Rpn2. Base assembly is mediated by four chaperones called p27, S5b, p28, and Rpn14 in mammals and Nas2, Hsm3, Nas6 and Rpn14 in yeast (the mammalian nomenclature is used in the figure). Each chaperone interacts with one or two Rpt subunits (indicated as 1–6) and guides their assembly into the base. The exact sequence of events during assembly is unclear. In one possible pathway (pathway I) favored by Funakoshi et al. (2009),Kaneko et al. (2009), and Murata et al. (2009), chaperone-bound subcomplexes coalesce to form a hexameric base that includes Rpn1, Rpn2, Rpn14, and p28. In this complex, the S5b precursor likely releases S5b, and Rpn2 displaces p27. The lid assembles independently by an unknown mechanism and completes the 19S along with S5a (Rpn10 in yeast). The 20S particle then displaces p28 and Rpn14 to form the active 26S proteasome. In an alternative pathway (pathway II) favored by Park et al. (2009) and Roelofs et al. (2009), the 20S particle serves as a template on which Rpn2, Rpt4, Rpt6, and Rpt3 (base precursor 2) assemble with the assistance of p28 and Rpn14 to form a subcomplex. This subcomplex is then joined by the S5b precursor and Rpt5 (base precursor 1) as well as the lid and S5a to form the 26S proteasome.