Perilous journey: a tour of the ubiquitin-proteasome system - PubMed (original) (raw)
Review
Perilous journey: a tour of the ubiquitin-proteasome system
Gary Kleiger et al. Trends Cell Biol. 2014 Jun.
Abstract
Eukaryotic cells are equipped to degrade proteins via the ubiquitin-proteasome system (UPS). Proteins become degraded upon their conjugation to chains of ubiquitin where they are then directed to the 26S proteasome, a macromolecular protease. The transfer of ubiquitin to proteins and their subsequent degradation are highly complex processes, and new research is beginning to uncover the molecular details of how ubiquitination and degradation take place in the cell. We review some of the new data providing insights into how these processes occur. Although distinct mechanisms are often observed, some common themes are emerging for how the UPS guides protein substrates through their final journey.
Keywords: E1-activating; E2-conjugating; E3-ligase; proteolysis; ubiquitin proteasome system.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Figures
Figure 1
(A) Schematic representation of the different modifications occurring at the carboxyl end of ubiquitin during ubiquitination. (i) RING (really interesting new gene) and RING-like E3s mediate the direct transfer of ubiquitin from the E2 onto the substrate; (ii) an additional _trans_-thioesterification step is mediated by HECT (homologous to E6-AP carboxyl terminus) and RBR (ring between ring) E3s before substrate ubiquitination. (B) Model for substrate ubiquitination mediated by RING and RING-like E3s. The conformation of ubiquitin on the E2 can be labile due to its flexible tail. Binding of the E2~ubiquitin (linked via a thioester bond) to the E3 serves to fasten the ubiquitin and its carboxyl tail against the E2, thereby accelerating the rate of ubiquitin transfer to substrate.
Figure 2
Proposed model for substrate recognition and processing by the proteasome. The schematic represents a cutaway view through the center of the 26S proteasome. When the proteasome is not bound to a ubiquitinated substrate (left), the 19S conformation places the Rpn11 (proteasome regulatory particle base subunit 11) active site (represented by the star outline) in a position that is inaccessible to the substrate translocation pore. Furthermore, the channel formed by a ring of six ATPases that promote substrate translocation (blue) is not properly aligned with the 20S aperture. When the proteasome binds to a ubiquitinated substrate, the conformation of the 19S is rearranged such that the unfolded protein can enter the 20S chamber and the Rpn11 active site (yellow star) can cleave the poly-ubiquitin chain. In this model, only substrates conjugated to poly-ubiquitin chains containing four or more protomers can be efficiently processed because only these chains have the minimal length that is necessary to span the distance between one of the two ubiquitin receptors (Rpn10 or Rpn13) and Rpn11. Upon removal of the ubiquitin chain, the substrate is translocated by the ATP-dependent action of the ATPases into the 20S subunit where it is hydrolyzed into short peptides.
Figure I
Catalysis of ubiquitin transfer.
Similar articles
- Ubiquitin-Proteasome Pathway and Muscle Atrophy.
Khalil R. Khalil R. Adv Exp Med Biol. 2018;1088:235-248. doi: 10.1007/978-981-13-1435-3_10. Adv Exp Med Biol. 2018. PMID: 30390254 Review. - Ubiquitin proteasome system in immune regulation and therapeutics.
Bhat SA, Vasi Z, Adhikari R, Gudur A, Ali A, Jiang L, Ferguson R, Liang D, Kuchay S. Bhat SA, et al. Curr Opin Pharmacol. 2022 Dec;67:102310. doi: 10.1016/j.coph.2022.102310. Epub 2022 Oct 23. Curr Opin Pharmacol. 2022. PMID: 36288660 Free PMC article. Review. - A critical discussion on the relationship between E3 ubiquitin ligases, protein degradation, and skeletal muscle wasting: it's not that simple.
Hughes DC, Goodman CA, Baehr LM, Gregorevic P, Bodine SC. Hughes DC, et al. Am J Physiol Cell Physiol. 2023 Dec 1;325(6):C1567-C1582. doi: 10.1152/ajpcell.00457.2023. Epub 2023 Nov 13. Am J Physiol Cell Physiol. 2023. PMID: 37955121 Review. - Degradation of the stress-responsive enzyme formate dehydrogenase by the RING-type E3 ligase Keep on Going and the ubiquitin 26S proteasome system.
McNeilly D, Schofield A, Stone SL. McNeilly D, et al. Plant Mol Biol. 2018 Feb;96(3):265-278. doi: 10.1007/s11103-017-0691-8. Epub 2017 Dec 21. Plant Mol Biol. 2018. PMID: 29270890 - A patent review of the ubiquitin ligase system: 2015-2018.
Li X, Elmira E, Rohondia S, Wang J, Liu J, Dou QP. Li X, et al. Expert Opin Ther Pat. 2018 Dec;28(12):919-937. doi: 10.1080/13543776.2018.1549229. Epub 2018 Nov 23. Expert Opin Ther Pat. 2018. PMID: 30449221 Free PMC article. Review.
Cited by
- Molecular glue-mediated targeted protein degradation: A novel strategy in small-molecule drug development.
Tan X, Huang Z, Pei H, Jia Z, Zheng J. Tan X, et al. iScience. 2024 Aug 21;27(9):110712. doi: 10.1016/j.isci.2024.110712. eCollection 2024 Sep 20. iScience. 2024. PMID: 39297173 Free PMC article. Review. - Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction.
Tyrna P, Procyk G, Szeleszczuk Ł, Młynarczuk-Biały I. Tyrna P, et al. Int J Mol Sci. 2024 Aug 16;25(16):8949. doi: 10.3390/ijms25168949. Int J Mol Sci. 2024. PMID: 39201634 Free PMC article. Review. - Combination of AID2 and BromoTag expands the utility of degron-based protein knockdowns.
Hatoyama Y, Islam M, Bond AG, Hayashi KI, Ciulli A, Kanemaki MT. Hatoyama Y, et al. EMBO Rep. 2024 Sep;25(9):4062-4077. doi: 10.1038/s44319-024-00224-4. Epub 2024 Aug 23. EMBO Rep. 2024. PMID: 39179892 Free PMC article. - Role of allogeneic hematopoietic cell transplantation in VEXAS syndrome.
Dias AL, Groarke EM, Hickstein D, Patel B. Dias AL, et al. Ann Hematol. 2024 Aug 22. doi: 10.1007/s00277-024-05942-2. Online ahead of print. Ann Hematol. 2024. PMID: 39168911 Review. - Aberrant protein aggregation in amyotrophic lateral sclerosis.
Wang H, Zeng R. Wang H, et al. J Neurol. 2024 Aug;271(8):4826-4851. doi: 10.1007/s00415-024-12485-z. Epub 2024 Jun 13. J Neurol. 2024. PMID: 38869826 Review.
References
- Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 2009;78:399–434. - PubMed
- Tokunaga F, et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat. Cell Biol. 2009;11:123–132. - PubMed
- Komander D, Rape M. The ubiquitin code. Annu. Rev. Biochem. 2012;81:203–229. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- P20 RR016464/RR/NCRR NIH HHS/United States
- 5P20RR016464-11/RR/NCRR NIH HHS/United States
- CAPMC/ CIHR/Canada
- 8 P20 GM103440-11/GM/NIGMS NIH HHS/United States
- P20 GM103440/GM/NIGMS NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources