Activity

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A Ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein which covalently attaches ubiquitin to a lysine residue on a target protein. The ubiquitin ligase is typically 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 which are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitiin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targetted 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.

Ubiquitination System

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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 generally 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

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The Anaphase-promoting complex (APC) and the SCF complex (for 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.

There are several "families" of E3 ubiquitin ligases; these families are comprised by members that have particular protein domains that are capable of binding the E2 conjugase, and thus forming a ubiquitination complex. For example, the Skp1-Cullin-Fbox protein complex referenced above is formed by a family of E3 ubiquitin ligases that have an "F-box" domain. Thus the full complex is calles an "SCF" complex, for Skp1, Cullin, and F-box containing protein. Other E3 ubiquitin ligase proteins include those that have a RING domain (for Really Interesting New Gene). RING domains bind the E2 conjugase, and may be required for the enzymatic activity of the E2-E3 complex. Other E3 ubiquitin ligase proteins include those that have a HECT domain.