Glucose-induced degradation protein 4 homolog (GID4)

Glucose-induced degradation protein 4 homolog (GID4) is a substrate receptor component of the CTLH (C-terminal to LisH) E3 ubiquitin ligase complex. Its principal function is to recognize specific N-terminal peptide motifs ("degrons"), most often starting with hydrophobic residues or proline, at the amino terminus of substrate proteins. Upon binding these degrons, GID4 recruits the substrate protein to the CTLH/GID complex, which then ubiquitinates the substrate and triggers its degradation by the proteasome[1][3][4][8]. This process plays a key role in cellular adaptation to metabolic changes (notably glucose availability in yeast) and in regulating cell proliferation through the turnover of proteins such as transcription factors. Recent research has identified small molecule binders of GID4, laying the foundation for targeted protein degradation (TPD) strategies in drug discovery. While several tool compounds (such as 16, 67, 88, 91, PFI-7) bind GID4 with good affinity, none have reached clinical development as therapeutic agents. The molecular basis for substrate recognition involves an eight-stranded β-barrel structure that forms a deep, plastic cavity capable of accommodating a range of peptide and small molecule ligands[1][4][6]. Disruption of GID4 or the CTLH complex affects cell cycle progression and can lead to dysregulation of cell proliferation, suggesting disease relevance, particularly in cancer biology[5]. Currently, GID4 is considered a promising target in the field of induced protein degradation, and its modulation may enable novel approaches to degrade disease-relevant proteins that possess appropriate N-terminal degrons[1][6][8].

Other names

C17orf39VID24VID2Vacuolar import and degradation protein 24 homologGID complex subunit 4 homologglucose-induced degradation protein 4 homologVID24 homologvacuolar import and degradation 24vacuolar import and degradation protein 24 homolog

Drugs or tool compounds bind GID4 and promote recruitment of target proteins to the E3 ubiquitin ligase complex, leading to ubiquitination and proteasomal degradation (as in PROTAC-like TPD strategies)[1][6] - Binders interact with the substrate recognition pocket, mimicking degron peptide motifs[1]