| Ubiquitin—protein ligase |
|
E3 ubiquitin ligase Cbl (blue) in complex with E2 (cyan) and substrate peptide (green). PDB entry 4a4c[1]
|
| Identifiers |
| EC number |
6.3.2.19 |
| CAS number |
74812-49-0 |
| Databases |
| IntEnz |
IntEnz view |
| BRENDA |
BRENDA entry |
| ExPASy |
NiceZyme view |
| KEGG |
KEGG entry |
| MetaCyc |
metabolic pathway |
| PRIAM |
profile |
| PDB structures |
RCSB PDB PDBe PDBsum |
| Gene Ontology |
AmiGO / EGO |
| Search |
| PMC |
articles |
| PubMed |
articles |
| NCBI |
proteins |
|
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. The ubiquitin is attached to a lysine on the target protein by an isopeptide bond. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology.
Contents
- 1 Overview
- 2 Ubiquitination system
- 3 Ubiquitin ligase families
- 4 Individual E3 ubiquitin ligases
- 5 See also
- 6 References
- 7 External links
Overview
In enzymology, an ubiquitin-protein ligase (EC 6.3.2.19) is an enzyme that catalyzes the chemical reaction
- ATP + ubiquitin + protein lysine AMP + diphosphate + protein N-ubiquityllysine
The 3 substrates of this enzyme are ATP, ubiquitin, and protein lysine, whereas its 3 products are AMP, diphosphate, and protein N-ubiquityllysine.
This enzyme belongs to the family of ligases, to be specific those forming carbon-nitrogen bonds as acid-D-amino-acid ligases (peptide synthases). The systematic name of this enzyme class is ubiquitin:protein-lysine N-ligase (AMP-forming). This enzyme is also called ubiquitin-activating enzyme. This enzyme participates in 3 metabolic pathways: ubiquitin-mediated proteolysis, Parkinson's disease, and Huntington's disease.
Ubiquitination system
Schematic diagram of the ubiquitylation system.
The ubiquitin ligase is referred to as an E3, and operates in conjunction with an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme. There is one major E1 enzyme, shared by all ubiquitin ligases, that uses ATP to activate ubiquitin for conjugation and transfers it to an E2 enzyme. The E2 enzyme interacts with a specific E3 partner and transfers the ubiquitin to the target protein. The E3, which may be a multi-protein complex, is, in general, responsible for targeting ubiquitination to specific substrate proteins. In some cases, it receives the ubiquitin from the E2 enzyme and transfers it to the target protein; in other cases, it acts by interacting with both the E2 enzyme and the substrate, but never itself receives the ubiquitin.
Ubiquitin ligase families
Humans have an estimated 500-1000 E3 ligases, which impart substrate specificity onto the E1 and E2.[2] The E3 ligases are classified into four families: HECT, RING-finger, U-box, and PHD-finger.[2] The RING-finger E3 ligases are the largest family and contain ligases such as the anaphase-promoting complex (APC) and the SCF complex (Skp1-Cullin-F-box protein complex). SCF complexes consist of four proteins: Rbx1, Cul1, Skp1, which are invariant among SCF complexes, and an F-box protein, which varies. Around 70 human F-box proteins have been identified.[3] F-box proteins contain an F-box, which binds the rest of the SCF complex, and a substrate binding domain, which gives the E3 its substrate specificity.[2]
Examples
- A RING (Really Interesting New Gene) domain binds the E2 conjugase and might be found to mediate enzymatic activity in the E2-E3 complex[4]
- An F-box domain (as in the SCF complex) binds the ubiquitinated substrate. (e.g., Cdc 4, which binds the target protein Sic1; Grr1, which binds Cln).[5]
- A HECT domain, which is involved in the transfer of ubiquitin from the E2 to the substrate.
Individual E3 ubiquitin ligases
- E3A
- mdm2
- Anaphase-promoting complex (APC)
- UBR5 (EDD1)
- SOCS/ BC-box/ eloBC/ CUL5/ RING
- LNXp80
- CBX4, CBLL1
- HACE1
- HECTD1, HECTD2, HECTD3
- HECW1, HECW2
- HERC1, HERC2, HERC3, HERC4
- HUWE1, ITCH
- NEDD4, NEDD4L
- PPIL2
- PRPF19
- PIAS1, PIAS2, PIAS3, PIAS4
- RANBP2
- RNF4
- RBX1
- SMURF1, SMURF2
- STUB1
- TOPORS
- TRIP12
- UBE3A, UBE3B, UBE3C
- UBE4A, UBE4B
- UBOX5
- UBR5
- WWP1, WWP2
See also
- Ubiquitin-activating enzyme
- Ubiquitin-conjugating enzyme
- ERAD
- Ubiquitin
References
- ^ Dou H, Buetow L, Hock A, Sibbet GJ, Vousden KH, Huang DT (2012). "Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl". Nat. Struct. Mol. Biol. 19 (2): 184–92. doi:10.1038/nsmb.2231. PMC 3880865. PMID 22266821.
- ^ a b c Nakayama KI, Nakayama K (May 2006). "Ubiquitin ligases: cell-cycle control and cancer". Nature Reviews Cancer 6: 369–381. doi:10.1038/nrc1881. PMID 16633365.
- ^ Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW (May 2006). "Systematic analysis and nomenclature of mammalian F-box proteins" (PDF). Genes & Development 18: 2573–2580. doi:10.1101/gad.1255304. PMID 15520277.
- ^ Ardley HC, Robinson PA (2005). "E3 ubiquitin ligases". ESSAYS IN BIOCHEMISTRY 41: 15–30. doi:10.1042/EB0410015. PMID 16250895.
- ^ Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ (July 1996). "SKP1 Connects Cell Cycle Regulators to the Ubiquitin Proteolysis Machinery through a Novel Motif, the F-Box" (PDF). Cell 86 (2): 263–274. doi:10.1016/S0092-8674(00)80098-7. PMID 8706131.
External links
- Quips article describing E3 Ligase function at PDBe
- Ubiquitin-Protein Ligases at the US National Library of Medicine Medical Subject Headings (MeSH)
- EC 6.3.2.19
|
Enzymes: CO CS and CN ligases (EC 6.1-6.3)
|
|
| 6.1: Carbon-Oxygen |
- Aminoacyl tRNA synthetase
- Tyrosine
- Tryptophan
- Threonine
- Leucine
- Isoleucine
- Lysine
- Alanine
- Valine
- Methionine
- Serine
- Aspartate
- D-alanine-poly(phosphoribitol) ligase
- Glycine
- Proline
- Cysteine
- Glutamate
- Glutamine
- Arginine
- Phenylalanine
- Histidine
- Asparagine
- Aspartate
- Glutamate
- Lysine
|
|
| 6.2: Carbon-Sulfur |
- Succinyl coenzyme A synthetase - Acetyl Co-A synthetase - Long fatty acyl CoA synthetase
|
|
| 6.3: Carbon-Nitrogen |
- Glutamine synthetase
- Ubiquitin ligase
- Cullin
- Von Hippel-Lindau tumor suppressor
- UBE3A
- Mdm2
- Anaphase-promoting complex
- UBR1
- Glutathione synthetase
- CTP synthase
- Adenylosuccinate synthase
- Argininosuccinate synthetase
- Holocarboxylase synthetase
- GMP synthase
- Asparagine synthetase
- Carbamoyl phosphate synthetase
- Gamma-glutamylcysteine synthetase
|
|
- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
|
|
|
|
