Ubiquitin ligase

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, among other functions.

Overview
In enzymology, an ubiquitin-protein ligase is an enzyme that catalyzes the chemical reaction


 * ATP + ubiquitin + protein lysine $$\rightleftharpoons$$ 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.

Structural studies
As of late 2007, 75 structures have been solved for this class of enzymes, with PDB accession codes, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and.

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, 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
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).
 * A HECT domain, which is involved in the transfer of ubiquitin from the E2 to the substrate.

Individual E3 ubiquitin ligases
LNXp80
 * E3A
 * mdm2
 * Anaphase-promoting complex (APC)
 * UBR5 (EDD1)
 * SOCS/ BC-box/ eloBC/ CUL5/ RING


 * 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