Targeted Protein Degradation: Principles and Applications of the Proteasome
Abstract
:1. Introduction
2. Ubiquitin
2.1. Type and Function of Ubiquitin Chains
2.1.1. Methionine 1
2.1.2. Lysine 6 (K6)
2.1.3. Lysine 11 (K11)
2.1.4. Lysine 27 (K27)
2.1.5. Lysine 29 (K29)
2.1.6. Lysine 33 (K33)
2.1.7. Lysine 48 (K48)
2.1.8. Lysine 63 (K63)
3. The Proteasome and Beyond
3.1. Assembly of the 20S Proteasome
3.2. Assembly of the 19S RP
3.3. Assembly of the 26S Proteasome
3.4. Steps Involved in Substrate Degradation via the 26S Proteasome
3.4.1. Ubiquitination
3.4.2. Recognition of Ubiquitin Chains
3.4.3. Deubiquitination
3.4.4. Gate Opening and Translocation
3.4.5. Proteolysis
3.5. Substrate Degradation via the 20S Proteasome
3.6. Mixed Proteasome
3.7. Immunoproteasome
3.8. Thymoproteasome
4. Proteasome Regulatory Proteins
4.1. Proteasome-Activating Proteins
4.1.1. 11S Regulatory Particle
4.1.2. PA200
4.1.3. Nuclear Respiratory Factor 1
4.1.4. Zinc Finger AN1-Type Containing 5
4.1.5. Tankyrase
4.2. Proteasome-Inhibiting Proteins
4.2.1. DJ-1
4.2.2. NAD(P)H:Quinone-Oxidoreductase 1
4.2.3. PI31
4.2.4. c-Abl
4.2.5. Bassoon
5. Proteasome Activity in Diseases
5.1. Neurodegenerative Disease
5.2. Muscle Atrophy and Cachexia
5.3. Chemoresistant Cells
5.4. Cancer Stem Cells
6. Therapeutic Modalities Targeting Proteasomes
6.1. Proteolysis-Targeting Chimera
6.2. Molecular Glues
6.3. Hydrophobic Tagging
7. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Proteasome | Ubiquitin | E3 Ligase | Substrate | Mediator | Disease | References |
---|---|---|---|---|---|---|
26S | dependent | MDM2 | p53 | RNF31 | Cancer | [46,51] |
HIF1α | Cancer | [47] | ||||
Siah2 | ASPP2 | Cancer | [52] | |||
PHD3 | Cancer | [53] | ||||
HIPK2 | Cancer | [49] | ||||
CHK2 | Cancer | [54] | ||||
HDAC3 | Neurodegenerative disease | [55] | ||||
Cullin3 | HIF1α | RhoBTB3 | Cancer | [56] | ||
ULK1 | KLHL20 | Cancer, Diabetes | [57] | |||
Roquin2 | ASK1 | Cancer | [50] | |||
VHL | HIF1α | Cancer | [58] | |||
KEAP1 | IKKβ | Cancer | [59] | |||
KPC1 | p105 | Cancer | [60] | |||
CHIP | sGC | Cardiovascular disease | [61] | |||
Smurf1 | PIPKIγ | Cancer | [62] | |||
CRL4 | GRK2 | Gβ2 | Cardiovascular disease | [63] | ||
WWP1 | KLF5 | Cancer | [64] | |||
Itch | Bid | Cancer | [65] | |||
COP1 | MTA1 | Cancer | [66] | |||
independent | ODC | Antizyme1 | Cancer | [67] | ||
TS | Cancer | [68] | ||||
20S | independent | p53 | Cancer | [69] | ||
p53 | Isg15 | Cancer | [70] | |||
p35 | Neurodegenerative disease | [71] | ||||
p21 | 14-3-3τ | Cancer | [72] | |||
tau | Neurodegenerative disease | [73] | ||||
α-synuclein | Neurodegenerative disease | [74] | ||||
c-Myc | Antizyme2 | Cancer | [75] | |||
IκBα | Cancer | [76] | ||||
Aurora-A | AURKAIP1 Antizyme1 | Cancer | [77,78] | |||
p130 | pp71 | Cancer | [79] | |||
Rb | MDM2 | Cancer | [80] | |||
SE | [81] |
Proteasome Regulation | Family | Protein |
---|---|---|
Activation | 11S | |
PA200 | ||
NRF1 | ||
ZFAND5 | ||
Tankyrase | ||
Inhibition | CCRs 1 | DJ-1 |
CCRs | NQO1 | |
PI31 | ||
c-Abl | ||
Bassoon | ||
CCRs | CBR3 | |
CCRs | KRas | |
CCRs | RhoA |
Protac | Sniper | Molecular Glue | Hydrophobic Tagging | |
---|---|---|---|---|
Degradation system | Ubiquitin–proteasome | |||
Active site in POIs | Not required | |||
Linker | Yes | Yes | No | Yes |
Molecular weight | 700–1000 Da | 700–1000 Da | <500 Da | <500 Da |
Feature | bivalent | Bivalent | monovalent | monovalent |
Advantages | Entire elimination of pathogenic proteins | |||
High selectivity | ||||
Low doses | ||||
Recycle | ||||
Disadvantages | Low tissue penetration | |||
Limited of E3 ligases | ||||
Lack of clinical data | ||||
Hook effect | ||||
Essential of target ubiquitination | ||||
Targets | AR 1 | AR | IKZF2 2 | AR |
ER 3 | BRD4 4 | ALK 5 | ||
BRD4 | Tau | |||
BTK 6 | SRC-1 7 | |||
Tau | Akt3 8 |
PROTAC | SMI 1 | Antibody | siRNA | |
---|---|---|---|---|
Molecular weight | ~1 kDa | <0.5 kDa | >150 kDa | 5–15 kDa |
Targeting intracellular proteins | Yes | Yes | No | Yes |
Active site of target proteins | No required | Required | Required | No required |
Elimination of target proteins | Yes | No | No | Yes |
Tissue penetration | Low | High | Low | Low |
Oral administration | Yes | Yes | No | No |
Selectivity | High | Low | High | High |
Doses | Low | High | High | Low |
Stability | High | High | Low | Low |
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Kim, Y.; Kim, E.-K.; Chey, Y.; Song, M.-J.; Jang, H.H. Targeted Protein Degradation: Principles and Applications of the Proteasome. Cells 2023, 12, 1846. https://doi.org/10.3390/cells12141846
Kim Y, Kim E-K, Chey Y, Song M-J, Jang HH. Targeted Protein Degradation: Principles and Applications of the Proteasome. Cells. 2023; 12(14):1846. https://doi.org/10.3390/cells12141846
Chicago/Turabian StyleKim, Yosup, Eun-Kyung Kim, Yoona Chey, Min-Jeong Song, and Ho Hee Jang. 2023. "Targeted Protein Degradation: Principles and Applications of the Proteasome" Cells 12, no. 14: 1846. https://doi.org/10.3390/cells12141846