The Quest for Substrates for SCF-Trcp2 Ubiquitin Ligase: Crosstalk between Phosphorylation and Ubiquitination

presented in: Keystone Symposia 2011, Keystone Colorado

Poly-ubiquitination is a post-translational modi_cation that marks proteins for proteasomal degradation. In this process, substrates are covalently modi_ed by ubiquitin on speci_c lysine residues by three enzymes sequentially. They are: ubiquitin activating enzymes (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligases (E3). It is the E3 enzyme that confers substrate speci_city to the ubiquitin proteasome system. The human genome encodes for approximately thirty three E2 ubiquitin-conjugating enzymes, two E1 ubiquitin activating enzymes and over seven-hundred E3s. The sheer size of the E3s family indicates that there is a huge repertoire of substrates for the ubiquitin-proteasome system.

SCF ligases are a class of E3 enzymes composed of Skp1, Cullin 1, a RING-_nger protein (Rbx1 or Rbx2) and a variable component known as the F-box protein. The F-box protein family recognizes and captures specific substrates that are subsequently ubiquitinated by E2 ubiquitin-conjugating enzymes. For a number of the well-studied F-box substrates, such as Fbw7, Skp2 and _-Trcp, substrate binding requires the presence of unique phosphorylated motifs (phosphodegrons) on the substrates, indicating crosstalk between phosphorylation and ubiquitination. For instance, β-Trcp is an F-box protein containing WD repeats that bind speci_c substrates haboring the DSpGXX(X)Sp motif.