| Full Name | Ubiquitin |
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| Gene Symbol | Ubiquitin family (UBA52, RPS27A, UBB, UBC) |
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| UniProt ID | [P0C0U5](https://www.uniprot.org/uniprot/P0C0U5) (UBC) |
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| PDB ID | [1UBQ](https://www.ebi.ac.uk/pdbe/1UBQ) |
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| Molecular Weight | 8.5 kDa (76 amino acids) |
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| Subcellular Localization | Cytoplasm, Nucleus, Mitochondria, Membrane |
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| Protein Family | Ubiquitin fold modifier (UFM) family |
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| Discovery | 1975, Gideon Goldstein |
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Ubiquitin is a highly conserved 76-amino acid protein that serves as the primary post-translational modification in eukaryotic cells, governing protein degradation, signaling, trafficking, and numerous other cellular processes. Discovered in 1975, ubiquitin was initially characterized as a protein that marks proteins for degradation via the proteasome. We now understand that ubiquitin signaling is vastly more complex, with different chain architectures specifying distinct cellular outcomes—earning ubiquitin the nickname "the ubiquitin code".
The ubiquitin system is essential for cellular homeostasis, with an estimated 5-10% of human genes dedicated to ubiquitin pathway components. Dysregulation of ubiquitin signaling is implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS.
- Amino acids: 76
- Molecular weight: 8,467 Da
- Sequence: Highly conserved across eukaryoths
- C-terminal Gly76: Required for isopeptide bond formation
- PDB: 1UBQ (first solved by X-ray crystallography)
- Fold type: β-grasp (β-grasp fold)
- Secondary structure: Five β-strands (β1-β5), one α-helix
- Stability: Exceptional—requires 6M guanidine HCl to denature
- Key surface: Lys residues (6, 11, 27, 29, 33, 48, 63) project from the β-sheet
| Feature |
Residues |
Function |
| Hydrophobic patch |
I44, V70, L8, L71 |
E2/E3 binding |
| Charged region |
D58, E64 |
Interactions |
| Lysine residues |
K6, K11, K27, K29, K33, K48, K63 |
Chain building |
| N-terminal Met |
M1 |
Linear chains |
¶ Chain Linkages and Functions
| Linkage |
Primary Function |
Key E2/E3 |
| K48 |
Proteasomal degradation |
UBE2K, UBE2D |
| K63 |
Signaling, endocytosis |
UBE2N/UBE2V1 |
| K11 |
Cell cycle, proteasome |
UBE2C |
| K27 |
Autophagy, stress |
HERC2 |
| K6 |
DNA damage |
UBE2N |
| K29 |
Lysosome, signaling |
UBE2O |
| K33 |
Synaptic function |
TRIM proteins |
| M1 |
NF-κB signaling |
LUBAC |
- Monomer: Single ubiquitin attached (signaling)
- Homotypic chains: Single linkage type
- Mixed chains: Multiple linkages
- Branched chains: Multiple linkages from one Ub
- Linear (M1): Head-to-tail polymerization
- Ubiquitination: E1 (activating) → E2 (conjugating) → E3 (ligase)
- Polyubiquitination: K48 chains signal for proteasome
- Degradation: 26S proteasome recognizes, unfolds, digests
- Recycling: Ubiquitin recycled by deubiquitinating enzymes
- NF-κB: K63, M1 chains for activation
- Wnt: K27, K29 for receptor trafficking
- DNA repair: K6, K48 for damage response
- mTOR: Complex regulation
- Cell cycle progression
- DNA replication and repair
- Immune signaling
- Apoptosis
- Synaptic plasticity
- Organelle quality control
- ER-associated degradation (ERAD)
- E1 (activating enzymes): ~10 in humans
- E2 (conjugating enzymes): ~40 in humans
- E3 (ligases): ~600-700 in humans
- Deubiquitinating enzymes (DUBs): ~100 in humans
- Substrate recognition: E3 ligases target specific proteins
- Ubiquitin activation: E1 thioester formation
- Ubiquitin transfer: E2~Ub to substrate
- Chain elongation: Additional Ub molecules added
- Proteasome binding: 19S regulatory particle recognizes K48 chains
- Unfolding and degradation: Substrate translocated into 20S core
- Ubiquitin recycling: DUBs cleave Ub for reuse
- Amyloid plaques: Ubiquitinated Aβ aggregates
- Neurofibrillary tangles: Ubiquitinated tau
- Proteasome impairment: Observed in AD brain
- Synaptic loss: Ubiquitin homeostasis disrupted
- Therapeutic approaches: Proteasome activators, DUB modulators
- Lewy bodies: Ubiquitinated α-synuclein inclusions
- Parkin mutations: Autosomal recessive PD
- PINK1-Parkin pathway: Mitochondrial quality control
- Lysosomal dysfunction: Autophagy-lysosome pathway
- Therapeutic target: Enhance protein clearance
- Mutant huntingtin: Ubiquitinated nuclear inclusions
- Transcription dysregulation: Altered ubiquitination
- Proteasome inhibition: Direct impairment
- Autophagy: Impaired clearance
- TDP-43 pathology: Ubiquitinated inclusions
- C9orf72: Dipeptide repeats affect proteostasis
- Proteasome dysfunction: Motor neuron vulnerability
- RNA binding proteins: Altered ubiquitination
- Proteasome activators: Enhance degraded protein clearance
- Proteasome inhibitors: Used in multiple myeloma
- DUB inhibitors/activators: Modulate ubiquitin pools
- E3 ligase modulators: Restore targeting
- mTOR inhibitors: Rapamycin, everolimus
- mTOR-independent: Trehalose, lithium
- TFEB activation: Gene therapy approaches
- Ubiquitin overexpression: Enhance clearance capacity
- E3 ligase delivery: Restore function
- DUB delivery: Increase ubiquitin recycling
Ubiquitin (Ubiquitin C/UBC) is ubiquitously expressed throughout the brain: