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Molecular mechanisms of proteasome assembly

Nature Reviews Molecular Cell Biology volume 10, pages 104–115 (2009)Cite this article

Key Points

  • The 26S proteasome is a eukaryotic large protein complex that is essential for regulated protein degradation in collaboration with the ubiquitin system. It consists of the catalytic 20S proteasome and the 19S regulatory particle, but how this large complex is assembled has been a mystery.

  • Recent studies have unveiled several proteasome-dedicated chaperones that are involved in efficient and correct assembly of the eukaryotic proteasome.

  • The mammalian proteasome assembling chaperone 1 (PAC1)–PAC2 heterodimer is suggested to be involved in the formation of α-rings, the earliest assembly intermediates to be observed during 20S proteasome biogenesis. At the same time, it prevents aberrant dimerization of α-rings.

  • The yeast proteasome biogenesis-associated 3 (Pba3)–Pba4 heterodimer (and presumably the mammalian PAC3–PAC4 complex) is also involved in α-ring formation by catalysing correct subunit orientation of the α-ring.

  • Yeast ubquitin-mediated proteolysis 1 (Ump1) and its human orthologue UMP1 have an important role in the dimerization of half-proteasomes. UMP1 is also shown to be required for β-ring formation on the α-ring in cooperation with the propeptides and carboxy-terminal extensions of β-subunits.

  • Compared with the 20S proteasome, the assembly of the 19S RP is largely unknown, but several molecules that affect the integrity of the 19S RP have been reported.

Abstract

The 26S proteasome is a highly conserved protein degradation machine that consists of the 20S proteasome and 19S regulatory particles, which include 14 and 19 different polypeptides, respectively. How the proteasome components are assembled is a fundamental question towards understanding the process of protein degradation and its functions in diverse biological processes. Several proteasome-dedicated chaperones are involved in the efficient and correct assembly of the 20S proteasome. These chaperones help the initiation and progression of the assembly process by transiently associating with proteasome precursors. By contrast, little is known about the assembly of the 19S regulatory particles, but several hints have emerged.

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Figure 1: Schematic diagram of the 26S proteasome.
Figure 2: Molecular structures of eukaryotic 20S proteasomes.
Figure 3: Model for proteasome assembly.
Figure 4: Structural basis of Pba3–Pba4 and PAC3.

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Acknowledgements

We are grateful to T. Mizushima, Nagoya City University, Nagoya, Japan, for preparing figures of crystal structures. This work was supported by grants to S.M., H.Y. and K.T. from the Ministry of Education, Science and Culture of Japan (MEXT) and the Target Protein Project of MEXT (to K.T.).

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Authors and Affiliations

  1. Department of Integrated Biology, Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan

    Shigeo Murata & Hideki Yashiroda

  2. Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, 113-8613, Tokyo, Japan

    Keiji Tanaka

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  1. Shigeo Murata
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Correspondence to Keiji Tanaka.

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Glossary

Caspase-like activity

Enzymatic activity that is similar to that of caspases — Cys proteases that have essential roles in apoptosis. β1 was first reported to cleave after Glu residues, and was thus termed peptidylglutamyl peptide hydrolase. Later, it was found that β1 also cleaves after Asp acid residues in substrates of caspases.

Trypsin-like activity

β2 cleaves after the basic amino acids Lys and Arg. As this activity resembles that of trypsin, a Ser protease that is secreted in pancreatic juice, it is referred to as 'trypsin-like' activity.

Chymotrypsin-like activity

β5 cleaves after hydrophobic amino acids. This activity resembles that of chymotrypsin, a Ser protease that is secreted in pancreatic juice, and is thus referred to as chymotrypsin-like activity.

AAA+ ATPase

(ATPase associated with diverse cellular activities). ATP-hydrolysing enzyme that contains one or two conserved ATP-binding domains, which are in turn comprised of conserved A and B motifs. AAA+ ATPases assemble into oligomeric assemblies (often hexamers) that form a ring-shaped structure with a central pore.

UBL

(Ubiquitin-like). A protein domain with motifs that have significant sequence and structural similarity to ubiquitin. Type 1 UBLs are comprised solely of this motif and generally work as modifiers that are covalently attached to target proteins, in a fashion similar to the ubiquitin. Type 2 UBLs are larger proteins that contain this motif as a part of the protein.

UBA

(Ubiquitin-association). A domain of ∼45 amino acids that adopts a structure that comprises a three α-helix bundle. The UBA domain binds to ubiquitin through a conserved hydrophobic surface patch.

Operon

A unit of genes in prokaryotes that is expressed as a single messenger RNA.

ERAD

(Endoplasmic reticulum-associated degradation). A system that ubiquitylates misfolded proteins in the endoplasmic reticulum for degradation by the 26S proteasome.

Unfolded protein response

A cellular stress response that is induced by the accumulation of unfolded proteins in the endoplasmic reticulum.

Cdc48

A chaperone-like AAA+ ATPase that is required for various cellular processes, such as cell cycle progression, homotypic membrane fusion and ERAD. The human counterpart of Cdc48 is valosin-containing protein.

Proteasome-activating nucleotidase

An AAA+ ATPase ring complex and archaeal regulatory particle triple-A homologue that opens the gate of 20S proteasomes and activates protein degradation.

PCI domain

The homology domain of unclear function that is present in several components of the proteasome, the COP9 signalosome and eukaryotic translation initiation factor 3.

COP9 signalosome

An eight-subunit protein complex that regulates protein ubiquitylation and turnover in various developmental and physiological contexts. Extensively characterized in plants but fundamental to all eukaryotes, this complex post-translationally modifies the cullin subunit of E3 ubiquitin ligases by cleaving the covalently coupled polypeptide Nedd8.

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Murata, S., Yashiroda, H. & Tanaka, K. Molecular mechanisms of proteasome assembly. Nat Rev Mol Cell Biol 10, 104–115 (2009). https://doi.org/10.1038/nrm2630

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