DEG_SPOP_SBC_1

SPOP SBC docking motif

SPOP is part of a multiprotein E3 ligase assembled with the cullin cul3. SPOP has two globular domains. Cullin E3 ligase binds to the BTB domain while the MATH domain directly recruits the substrates of the E3 ligase complex for ubiquitination. Substrate have a degron termed the SPOP-binding consensus (SCB) that binds to the MATH domain. The SCB degron is an unusual ST-rich peptide motif and is known in several substrate proteins including MacroH2A, the transcriptional regulators Ci/GLI3, the phosphatase Puc and DAXX. The SPOP/Cul3 E3 ligase complex is an important regulator of the cell cycle. Due to the high conformational flexibility of the SPOP complex substrates with several SCB configurations can be polyubiquinated.

The degron targeted by SPOP is known as the SPOP-binding consensus (SBC). It binds to the MATH domain of the Speckle-type POZ protein (SPOP) that is part of the cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex. This mediates the ubiquitination of target proteins, leading to their proteasomal degradation. The peptide motif is unusually S/T rich while there is a hydrophobic amino acid located at the start of the peptide sequence. Therefore, SPOPMATH-SBC interactions are anchored with both hydrophobic and polar interactions. In complex with Cul3, the binding of SPOP to the motif leads to the proteasomal degradation of DAXX, PUC, Ci, GLI2 and GLI3 as well as of MacroH2A. While in the case of MacroH2A the motif was found only once in the protein sequence, it can be found two or three times in most of the other SPOP substrates. Since a dimeric SPOP BTB domain can assemble with two molecules of Cul3 it generates a dimeric ubiquitin ligase containing two substrate-binding sites (Zhuang,2009). As with other short motifs (SBC spans only 5 amino acids) database searches are likely to return numerous false positive hits. All experimentally verified motifs found in the SPOP substrates were located in natively disordered regions of the substrate proteins. In case of MacroH2A, alignments showed that the motif was highly conserved between many species. This and conservation in other substrates allowed the motif positions to be defined.

MATH (PF00917) MATH domain (Stochiometry: 1 : 1)