10779/crick.11558262.v1 Michael Lim Michael Lim Joseph A Newman Joseph A Newman Hannah L Williams Hannah L Williams Laura Masino Laura Masino Hazel Aitkenhead Hazel Aitkenhead Angeline E Gravard Angeline E Gravard Opher Gileadi Opher Gileadi Jesper Q Svejstrup Jesper Q Svejstrup A ubiquitin-binding domain that binds a structural fold distinct from that of ubiquitin. The Francis Crick Institute 2020 CUE domain KAP1 SMARCAD1 TIF1β TRIM28 UBA domain ubiquitin ubiquitin-binding domain Svejstrup FC001166 SB PRT-ack PC-ack CS-ack 06 Biological Sciences 08 Information and Computing Sciences 03 Chemical Sciences Biophysics 2020-01-09 11:44:16 Journal contribution https://crick.figshare.com/articles/journal_contribution/A_ubiquitin-binding_domain_that_binds_a_structural_fold_distinct_from_that_of_ubiquitin_/11558262 Ubiquitylation, the posttranslational linkage of ubiquitin moieties to lysines in target proteins, helps regulate a myriad of biological processes. Ubiquitin, and sometimes ubiquitin-homology domains, are recognized by ubiquitin-binding domains, including CUE domains. CUE domains are thus generally thought to function by mediating interactions with ubiquitylated proteins. The chromatin remodeler, SMARCAD1, interacts with KAP1, a transcriptional corepressor. The SMARCAD1-KAP1 interaction is direct and involves the first SMARCAD1 CUE domain (CUE1) and the RBCC domain of KAP1. Here, we present a structural model of the KAP1 RBCC-SMARCAD1 CUE1 complex based on X-ray crystallography. Remarkably, CUE1, a canonical CUE domain, recognizes a cluster of exposed hydrophobic and surrounding charged/amphipathic residues on KAP1, which are presented in the context of a coiled-coil domain, not in a structure resembling ubiquitin. Together, these data suggest that CUE domains may have a wider function than simply recognizing ubiquitin and the ubiquitin-fold.