The thalidomide-binding domain of cereblon defines the CULT domain family and is a new member of the ?-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 ?-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 ?-meanders packing at a roughly right angle and coordinating a zinc ion at their apex. A ?-hairpin inserted into the first ?-meander extends across the bottom of the structure towards the C-terminal edge of the second ?-meander, with which it forms a cradle-shaped binding site that is topologically conserved in all members of this fold. We name this the ?-tent fold for the striking arrangement of its constituent ?-sheets. The fold has internal pseudosymmetry, raising the possibility that it arose by duplication of a subdomain-sized fragment.

SUBMITTER: Lupas AN 

PROVIDER: S-EPMC4287342 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature