Reactome | Proteasome assembly

Proteasome assembly

Stable Identifier

R-HSA-9907900

Type

Pathway

Species

Homo sapiens

ReviewStatus

3/5

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Proteasome comes in several varieties. From the most ubiquitous 26S proteasome, through P28 proteasomes, to the tissue-specific proteasomes such as immunoproteasome, thymoproteasome, and spermatoproteasome.

26S proteasome, responsible for most aspects of ubiquitin-dependent regulatory and quality-control protein degradation in cells, is a 2.6-MDa protein complex that consists of a barrel-shaped proteolytic 20S core particle (20S CP) of 28 subunits capped on one or both ends by a 19S regulatory particle (19S RP) comprised of at least 19 subunits (reviewed in Tomko and Hochstrasser 2013). The 19S RP, which consists of a base and a lid, coordinates substrate recognition, removal of substrate polyubiquitin chains, and substrate unfolding and translocation into the 20S CP for degradation (reviewed in Tomko and Hochstrasser 2013).

The 20S CP consists of four axially stacked heteroheptameric rings - two inner and two outer rings (reviewed in Tomko and Hochstrasser 2013). Inner rings contain seven distinct beta-subunits (beta-1-7, officially PSMB1-7 in humans, where beta-1 corresponds to PSMB6, beta-2 to PSMB7, beta-3 to PSMB3, beta-4 to PSMB2, beta-5 to PSMB5, beta-6 to PSMB1, and beta-7 to PSMB4), while the outer rings contain seven distinct alpha-subunits (alpha1-7, officially PSMA1-7 in humans, where alpha-1 corresponds to PSMA6, alpha-2 to PSMA2, alpha-3 to PSMA4, alpha-4 to PSMA7, alpha-5 to PSMA5, alpha-6 to PSMA1, and alpha-7 to PSMA3).

P28 proteasomes consist of the 20S CP and a P28 regulatory particle that does not have a ubiquitin receptor and comes in at least two different types of heptamers: P28-alpha-beta, composed of PSME1 (P28alpha) and PSME2 (P28beta), and P28-gamma, composed of PSME3 (P28gamma). P28 proteasomes are thought to be important for rapid degradation of misfolded proteins under conditions of oxidative stress (reviewed in Thomas et al. 2023).

In the immunoproteasome, the 20S CP inner ring subunits with proteolytic activity, PSMB6 (beta-1), PSMB7 (beta-2), and PSMB5 (beta-5), are substituted with PSMB9 (beta-1i), PSMB10 (beta-2i), and PSMB8 (beta-5i), respectively, and this variation of the core particle is known as 20S iCP. The immunoproteasome generates substrate cleavage patterns that enhance loading of peptides onto the class I major histocompatibility complex (MHC I) for immune presentation to killer T cells (reviewed in Tomko and Hochstrasser 2013). Immunoproteasomes utilize the P28 regulatory particle (Chen et al. 2021).

In the thymoproteasome, expressed in the thymus, the 20S CP inner ring proteolytic subunits PSMB6 (beta-1), PSBM7 (beta-2), and PSMB5 (beta-5), are replaced with PSMB9 (beta-1i), PSMB10 (beta-2i) and PSMB11 (beta-5t), respectively, and this variation of the core particle is known as 20S tCP. Thymoproteasomes appear to increase the repertoire of self peptides for positive selection during T cell development in the thymus (reviewed in Tomko and Hochstrasser 2013). The regulatory particle used by thymoproteasomes is not known.

In the spermatoproteasome, specifically expressed in differentiating spermatocytes, the outer ring subunit PSMA7 (alpha-4) is replaced with PSMA8 (alpha-4s). Spermatoproteasomes use the 19S RP and include an additional component, PSME4 (PA200) (Kniepert and Groettrup 2014).

An important endogenous inhibitor of the catalytic activity of 20S CP is the protein PSMF1 (PI31) (Hsu et al. 2023).

For a high-throughput study of subunit-subunit interactions in the human 26S proteasome, please refer to Chen et al. 2008, and for the cryogenic electron microscope (cryo-EM) studies of the human 26S proteasome please refer to Lu et al. 2017 and Adolf et al. 2024.

Literature References

PubMed ID	Title	Journal	Year
28689658	Conformational Landscape of the p28-Bound Human Proteasome Regulatory Particle Lu, Y, Wu, J, Dong, Y, Chen, S, Sun, S, Ma, YB, Ouyang, Q, Finley, D, Kirschner, MW, Mao, Y	Mol Cell	2017
38600324	Visualizing chaperone-mediated multistep assembly of the human 20S proteasome Adolf, F, Du, J, Goodall, EA, Walsh, RM, Rawson, S, von Gronau, S, Harper, JW, Hanna, J, Schulman, BA	Nat Struct Mol Biol	2024
37759726	Structure, Function, and Allosteric Regulation of the 20S Proteasome by the 11S/PA28 Family of Proteasome Activators Thomas, T, Salcedo-Tacuma, D, Smith, DM	Biomolecules	2023
24286712	The unique functions of tissue-specific proteasomes Kniepert, A, Groettrup, M	Trends Biochem Sci	2014
18186020	Subunit-subunit interactions in the human 26S proteasome Chen, C, Huang, C, Chen, S, Liang, J, Lin, W, Ke, G, Zhang, H, Wang, B, Huang, J, Han, Z, Ma, L, Huo, K, Yang, X, Yang, P, He, F, Tao, T	Proteomics	2008
33531497	Cryo-EM of mammalian PA28αβ-iCP immunoproteasome reveals a distinct mechanism of proteasome activation by PA28αβ Chen, J, Wang, Y, Xu, C, Chen, K, Zhao, Q, Wang, S, Yin, Y, Peng, C, Ding, Z, Cong, Y	Nat Commun	2021
23495936	Molecular architecture and assembly of the eukaryotic proteasome Tomko, RJ, Hochstrasser, M	Annu Rev Biochem	2013
37236357	Ηigh-resolution structure of mammalian PI31-20S proteasome complex reveals mechanism of proteasome inhibition Hsu, HC, Wang, J, Kjellgren, A, Li, H, DeMartino, GN	J Biol Chem	2023