InterPro domain: IPR039515

NOT4, also known as CCR4-associated factor 4, E3 ubiquitin-protein ligase CNOT4, or potential transcriptional repressor NOT4, is a component of the multifunctional CCR4-NOT complex, a global regulator of RNA polymerase II transcription. It associates with polysomes and contributes to the negative regulation of protein synthesis [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. NOT4 functions as an E3 ubiquitin-protein ligase that interacts with a specific E2, Ubc4/5 in yeast, and the orthologue UbcH5B in humans, and ubiquitylates a wide range of substrates, including ribosome-associated factors [ 9 ]. Thus, it plays a role in cotranslational quality control (QC) through ribosome-associated ubiquitination and degradation of aberrant peptides. NOT4 contains a C4C4-type RING finger motif, whose overall folding is similar to that of the C3HC4-type RING-HC finger, a central RNA recognition motif (RRM), and a C-terminal domain predicted to be unstructured [ 10 ].

1. The structure of the C4C4 ring finger of human NOT4 reveals features distinct from those of C3HC4 RING fingers. J. Biol. Chem. 276, 10185-90
2. Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits. Nucleic Acids Res. 28, 809-17
3. Identification of a ubiquitin-protein ligase subunit within the CCR4-NOT transcription repressor complex. EMBO J. 21, 355-64
4. Not4 enhances JAK/STAT pathway-dependent gene expression in Drosophila and in human cells. FASEB J. 26, 1239-50
5. Not4-dependent translational repression is important for cellular protein homeostasis in yeast. EMBO J. 34, 1905-24
6. Role of Ccr4-Not complex in heterochromatin formation at meiotic genes and subtelomeres in fission yeast. Epigenetics Chromatin 8, 28
7. The role of the E3 ligase Not4 in cotranslational quality control. Front Genet 5, 141
8. The Not4 E3 ligase and CCR4 deadenylase play distinct roles in protein quality control. PLoS ONE 9, e86218
9. Architecture of the ubiquitylation module of the yeast Ccr4-Not complex. Structure 23, 921-928
10. Structural model of the UbcH5B/CNOT4 complex revealed by combining NMR, mutagenesis, and docking approaches. Structure 12, 633-44