Structural insights on the dynamics of proteasome formation

Abstract

Molecular organization in biological systems comprises elaborately programmed processes involving metastable complex formation of biomolecules. This is exemplified by the formation of the proteasome, which is one of the largest and most complicated biological supramolecular complexes. This biomolecular machinery comprises approximately 70 subunits, including structurally homologous, but functionally distinct, ones, thereby exerting versatile proteolytic functions. In eukaryotes, proteasome formation is non-autonomous and is assisted by assembly chaperones, which transiently associate with assembly intermediates, operating as molecular matchmakers and checkpoints for the correct assembly of proteasome subunits. Accumulated data also suggest that eukaryotic proteasome formation involves scrap-and-build mechanisms. However, unlike the eukaryotic proteasome subunits, the archaeal subunits show little structural divergence and spontaneously assemble into functional machinery. Nevertheless, the archaeal genomes encode homologs of eukaryotic proteasome assembly chaperones. Recent structural and functional studies of these proteins have advanced our understanding of the evolution of molecular mechanisms involved in proteasome biogenesis. This knowledge, in turn, provides a guiding principle in designing molecular machineries using protein engineering approaches and de novo synthesis of artificial molecular systems.

Molecular and Structural Basis of the Proteasome α Subunit Assembly Mechanism Mediated by the Proteasome-Assembling Chaperone PAC3-PAC4 Heterodimer

“…The correct arrangement of the proteasomal subunits is essential to the proper functioning of eukaryotic proteasomes. There is considerable evidence that the assembly of the eukaryotic 26S proteasome does not proceed spontaneously, but is mediated by several assembly chaperones [5,6,7,8]. The formation of the 20S CP is assisted by five proteasome-specific chaperones: PAC1–PAC4 and POMP in humans; Pba1–Pba4 and Ump1 in yeast.…”

Genome-wide identification, characterisation and expression profiling of the ubiquitin-proteasome genes in Biomphalaria glabrata

“…Nineteen genes from the RPN and RPT groups were identified in our analysis ( Table I ), encompassing sequences of major importance such as RPN-11, RPN-15 and RPN-3, involved with target substrate recognition and removal of the ubiquitin chain formed. 15 , 30 In the same sense, some RPT subunits, such as rpt-2 and rpt-5 were also found in the data of B. glabrata ; however, they are related to activation of the 20S nucleus. 31 The results of this work show that RPT shares the conserved AAA domain, but not of an active site, structural motif or catalytic cleft, inferring that the function of these molecules was linked to the sequence that the conserved domain possesses [ (Fig.…”

Mutational and Combinatorial Control of Self-Assembling and Disassembling of Human Proteasome α Subunits

“…During evolutionary processes, the building blocks of these homo-oligomers acquire diversity in sequence and structure, maintaining their assembling properties. The proteasome system is one of the best examples demonstrating this concept [6,7,8].…”

“…The proteasome is a huge protein complex harboring a proteolytic chamber termed the 20S core particle. This 20S core particle comprises the α- and β-rings, two types of heptameric rings arranged as a cylindrical, four-layered αββα structure [6,7,8,9,10,11,12,13]. In the archaea, the heptameric α-ring is composed of seven identical α subunits and the heptameric β-ring is composed of one or two kinds of β subunits.…”

“…In contrast, in eukaryotes, both the α- and the β-rings are heteroheptamers composed of seven different but homologous subunits, i.e., α1–α7 and β1–β7. Assembly of these subunits is not an autonomous process but is assisted by several chaperones operating as molecular matchmakers and checkpoints [8,11,13,15,16,17,18,19,20,21].…”