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PROSITE documentation PDOC51788 [for PROSITE entry PS51788]

CULT domain profile





Description

Despite having caused one of the greatest medical catastrophies of the last century through its teratogenic side-effects, thalidomide continues to be an important agent in the treatment of leprosy and cancer. 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 involvment in brain development and to its Lon N-terminal domain (see <PDOC51787>). 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 γ-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 [1,2,3,4].

The CULT domain is a member of the β-tent fold, which consists of two four-stranded, antiparallel β-sheets that are oriented at an approximately right angle and pinned together at the top via a structural zinc ion (see <PDB:5AMH>). The thalidomide binding site is formed within the larger, C-terminal β-sheet. A third of the domain, including the thalidomide binding pocket, only folds upon ligand binding [1,2,3,4].

The profile we developed covers the entire CULT domain.

PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html --------------------------------------------------------------------------------.

Last update:

January 2016 / First entry.

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Technical section

PROSITE method (with tools and information) covered by this documentation:

CULT, PS51788; CULT domain profile  (MATRIX)


References

1AuthorsHartmann M.D. Boichenko I. Coles M. Zanini F. Lupas A.N. Hernandez Alvarez B.
TitleThalidomide mimics uridine binding to an aromatic cage in cereblon.
SourceJ. Struct. Biol. 188:225-232(2014).
PubMed ID25448889
DOI10.1016/j.jsb.2014.10.010

2AuthorsChamberlain P.P. Lopez-Girona A. Miller K. Carmel G. Pagarigan B. Chie-Leon B. Rychak E. Corral L.G. Ren Y.J. Wang M. Riley M. Delker S.L. Ito T. Ando H. Mori T. Hirano Y. Handa H. Hakoshima T. Daniel T.O. Cathers B.E.
TitleStructure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.
SourceNat. Struct. Mol. Biol. 21:803-809(2014).
PubMed ID25108355
DOI10.1038/nsmb.2874

3AuthorsLupas A.N. Zhu H. Korycinski M.
TitleThe thalidomide-binding domain of cereblon defines the CULT domain family and is a new member of the beta-tent fold.
SourcePLoS Comput. Biol. 11:E1004023-E1004023(2015).
PubMed ID25569776
DOI10.1371/journal.pcbi.1004023

4AuthorsHartmann M.D. Boichenko I. Coles M. Lupas A.N. Hernandez Alvarez B.
TitleStructural dynamics of the cereblon ligand binding domain.
SourcePLoS ONE 10:E0128342-E0128342(2015).
PubMed ID26024445
DOI10.1371/journal.pone.0128342



PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see prosite_license.html.

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