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Ubiquitin—protein ligase 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 A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome. In general, the ubiquitin ligase is involved in polyubiquitination: A second ubiquitin is attached to the first, a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin which is recognized by the proteasome. However, Lys63 can also be used, and chains using this lysine are important for DNA repair, amongst other functions. Contents 1 Overview 2 Structural studies 3 Ubiquitination system 4 Ubiquitin ligase families 4.1 Examples 5 Individual E3 ubiquitin ligases 6 See also 7 References 8 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, specifically 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. Structural studies As of late 2007, 75 structures have been solved for this class of enzymes, with PDB accession codes 1A3S, 1AYZ, 1C4Z, 1FBV, 1FXT, 1FZY, 1I7K, 1IYF, 1J7D, 1JAS, 1JAT, 1JBB, 1KPS, 1PZV, 1Q34, 1QCQ, 1TTE, 1U9A, 1U9B, 1UMH, 1UMI, 1UR6, 1W4U, 1WD2, 1WZV, 1WZW, 1X23, 1XR9, 1Y6L, 1Y8X, 1YH6, 1YLA, 1YRV, 1Z2U, 1Z3D, 1Z5S, 1Z6U, 1ZDN, 1ZUO, 2A4D, 2A7L, 2AAK, 2AWF, 2AYV, 2BEP, 2BF8, 2C4O, 2C4P, 2CLW, 2CYX, 2E2C, 2EKE, 2ESK, 2ESO, 2ESP, 2ESQ, 2F4W, 2FO3, 2FUH, 2GJD, 2GMI, 2GRN, 2GRO, 2GRP, 2GRQ, 2GRR, 2H2Y, 2O25, 2OB4, 2OGB, 2ONU, 2UCZ, 2UYZ, 2Z6O, and 2Z6P. Ubiquitination 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, which 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. Schematic diagram of the ubiquitylation system. Ubiquitin ligase families The anaphase-promoting complex (APC) and the SCF complex (Skp1-Cullin-F-box protein complex) are two examples of ubiquitin ligase protein scaffold involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome. Each contains particular protein domains capable of binding the E2 conjugase, as well as a substrate-specific domain for binding the target. Many E2- and substrate-binding domains exist. This wide variety has been discovered to fall into specific groups called ubiquitin-ligase families. 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 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).[1] 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 HACE1 HECTD1, HECTD2, HECTD3 HECW1, HECW2 HERC1, HERC2, HERC3, HERC4 HUWE1, ITCH NEDD4, NEDD4L PPIL2 PRPF19 PIAS1, PIAS2, PIAS3, PIAS4 RANBP2 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 ^ Bai, Chang; Partha Sen, Kay Hofmann, Lei Ma, Mark Goebl, J. Wade Harper, Stephen J. Elledge (1996-07). "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. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WSN-4195BWM-D-J&_cdi=7051&_user=145269&_orig=search&_coverDate=07%2F26%2F1996&_qd=1&_sk=999139997&view=c&wchp=dGLbVzb-zSkWz&md5=b76e13fd90d5461e65f8b62ea48cba95&ie=/sdarticle.pdf. Retrieved 2009-02-09.  External links MeSH Ubiquitin-Protein+Ligases EC 6.3.2.19 v · d · eEnzymes: 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 (I, II) - Gamma-glutamylcysteine synthetase B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6 v · d · ePosttranslational modification Chaperones/ protein folding Heat shock proteins/ Chaperonins Hsp10/GroES (Early pregnancy factor) · Hsp27 · Hsp47 · HSP60/GroEL Hsp40/DnaJ (A1, A2, A3, B1, B2, B11, B4, B6, B9, C1, C3, C5, C6, C7, C10, C11, C13, C14, C19) Hsp70 (1A, 1B, 1L, 2, 4, 4L, 5, 6, 7, 8, 9, 12A, 14) Hsp90 (α1, α2, β, ER, TRAP1) Other Alpha crystallin · Clusterin · Survival of motor neuron (SMN1, SMN2) Protein targeting Signal peptide Ubiquitin E1 Ubiquitin-activating enzyme (UBA1, UBA2, UBA3, UBA5, UBA6, UBA7, ATG7, NAE1, SAE1) E2 Ubiquitin-conjugating enzyme (A • B • C • D1, D2, D3 • E1, E2, E3 • G1, G2 • H • I • J1, J2 • K • L1, L2, L3, L4, L6 • M • N • O • Q1, Q2 • R1 (CDC34), R2 • S • V1, V2 • Z) E3 Ubiquitin ligase (VHL, Cullin, CBL, MDM2, FANCL, UBR1) Deubiquitinating enzyme: Ataxin 3 • USP6 • CYLD ATG3 • BIRC6 • UFC1 Other SUMO protein see also posttranslational modification disorders B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)