Domain

CULT domain (IPR034750)

Short name: CULT

Overlapping homologous superfamilies

None.

Domain relationships

Description

The cereblon protein, originally identified in a screen for mutations causing mild mental retardation, is a major target of thalidomide and its derivatives, and is responsible for the teratogenic effects of the drug. Cereblon owes its name to its involvement in brain development and to its Lon N-terminal domain. Cereblon proteins occur throughout eukaryotes, however not in fungi. Cereblon is a cofactor of damaged DNA-binding protein 1 (DDB1), which acts as the central component of an E3 ubiquitin ligase complex and regulates the selective degradation of key proteins in DNA repair, replication and transcription. Binding of thalidomide to a C-terminal region in cereblon alters the E3 ubiquitin ligase activity of the complex, which may in turn cause its teratogenic effects. The thalidomide-binding region of cereblon is a conserved domain, CULT (for Cereblon domain of Unknown activity, binding cellular Ligands and Thalidomide), carrying several invariant cysteine and tryptophan residues. The CULT domain is also found as the sole domain in a family of secreted proteins from animals and in a family of bacterial proteins occurring primarily in gamma-proteobacteria. Given the invariant nature of the CULT domain between animals and bacteria, a natural ligand universal to all domains of life seems plausible. The nature of the binding pocket, an aromatic cage of three tryptophan residues, suggests a role in the recognition of cationic ligands [PMID: 25448889, PMID: 25108355, PMID: 25569776, PMID: 26024445].

The CULT domain is a member of the beta-tent fold, which consists of two four-stranded, antiparallel beta-sheets that are oriented at an approximately right angle and pinned together at the top via a structural zinc ion. The thalidomide binding site is formed within the larger, C-terminal beta-sheet. A third of the domain, including the thalidomide binding pocket, only folds upon ligand binding [PMID: 25448889, PMID: 25108355, PMID: 25569776, PMID: 26024445].

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
CDD
PROSITE profiles