title: The thalidomide-binding domain of cereblon defines the CULT domain family and is a new member of the β-tent fold.
abstract: 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 protein cereblon, which forms an E3 ubiquitin ligase compex together with damaged DNA-binding protein 1 (DDB1) and cullin 4A, has been recently indentified as a primary target of thalidomide and its C-terminal part as responsible for binding thalidomide within a domain carrying several invariant cysteine and tryptophan residues. This domain, which we name CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide), is also found in a family of secreted proteins from animals and in a family of bacterial proteins occurring primarily in δ-proteobacteria. Its nearest relatives are yippee, a highly conserved eukaryotic protein of unknown function, and Mis18, a protein involved in the priming of centromeres for recruitment of CENP-A. Searches for distant homologs point to an evolutionary relationship of CULT, yippee, and Mis18 to proteins sharing a common fold, which consists of two four-stranded β-meanders packing at a roughly right angle and coordinating a zinc ion at their apex. A β-hairpin inserted into the first β-meander extends across the bottom of the structure towards the C-terminal edge of the second β-meander, with which it forms a cradle-shaped binding site that is topologically conserved in all members of this fold. We name this the β-tent fold for the striking arrangement of its constituent β-sheets. The fold has internal pseudosymmetry, raising the possibility that it arose by duplication of a subdomain-sized fragment.
authors.affiliation: Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Tuebingen, Germany.
authors.forename: Andrei N
authors.initials: AN
authors.lastname: Lupas
authors.affiliation: Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Tuebingen, Germany.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Tuebingen, Germany.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Korycinski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013792:Thalidomide / Q000737:chemistry* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D002352:Carrier Proteins; D029721:Drosophila Proteins; C428623:Yippee protein, Drosophila; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases