The thalidomide-binding domain of cereblon defines the CULT domain family and is a new member of the β-tent fold.

Andrei N Lupas,Mateusz Korycinski,Hongbo Zhu,Nick Grishin

doi:10.1371/journal.pcbi.1004023

Andrei N Lupas, Mateusz Korycinski + Show 2 more

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https://doi.org/10.1371/journal.pcbi.1004023

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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.

Highlights

Thalidomide was provided to pregnant women as an antinausea and sedative drug from 1957 to 1962, and was available over the counter in many countries
In 2010, Handa and co-workers showed in a landmark study that cereblon, a protein originally identified in a screen for mutations causing mild mental retardation [10], is a major target of thalidomide and is responsible for the teratogenic effects of the drug [11]
In the 2010 study, Handa and co-workers showed that cereblon is a cofactor of damaged DNAbinding 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 [12]

Summary

Introduction

Thalidomide was provided to pregnant women as an antinausea and sedative drug from 1957 to 1962, and was available over the counter in many countries It was withdrawn after it became apparent that it had caused a range of birth defects in many newborns, with over 10,000 cases reported from more than 46 countries [1,2]. Binding of thalidomide to a C-terminal region in cereblon inhibits the E3 ubiquitin ligase activity of the complex and leads to developmental limb defects in chicks and zebrafish [11]. Point mutations in this region, which abolish thalidomide binding, but allow the continued formation of the E3 complex, restore ubiquitination and prevent the teratogenic activities of thalidomide

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