Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Figure 1

Enzymatic cascade leading to substrate ubiquitination. Three sets of enzymes are required for ubiquitination of a targeted substrate: ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-ligase (E3) enzymes. There are two main classes of E3 enzymes, the RING and HECT classes, which differ in the manner by which they transfer Ub to a target substrate. Once a Ub molecule is conjugated to its target protein, additional Ub molecules can be attached to form chains (see Figure 2 for a more detailed illustration of Ub binding). However, since ubiquitination is a reversible process, once Ub is attached, deubiquitinating enzymes (DUBs) can then hydrolyze the isopeptide bond between Ub and its target protein (shown by the small lightning bolt) and thus return the protein to its previous state and release Ub. Substrates that contain polyUb chains are often targeted to the proteasome, where they are bound and subsequently degraded. The proteasome is composed of a catalytic 20S core particle structure and two 19S regulatory caps which together are collectively termed the 26S proteasome. While some polyubiquitinated proteins can be bound directly through polyUb binding subunits on the proteasome, others must be shuttled to the proteasome via adaptor proteins (the binding site for Ub and adaptors is represented by a yellow circle). Once the substrate is bound to the proteasome, many ATPase subunits that make up the proteasome utilize ATP to unfold the protein, simultaneously deubiquitinating the protein and releasing Ub while cleaving the protein into small peptide fragments.